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Dou JY, Zhou MJ, Xuan MY, Guo J, Liu SH, Lian LH, Cui ZY, Nan JX, Wu YL. Astilbin alleviates hepatic fibrosis through PXR-PINK1/Parkin pathway: A new strategy by regulating hepatic stellate cells-macrophage crosstalk. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 135:156144. [PMID: 39405612 DOI: 10.1016/j.phymed.2024.156144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 09/21/2024] [Accepted: 10/07/2024] [Indexed: 12/01/2024]
Abstract
BACKGROUND Astilbin (ATB), a natural dihydroflavonol compound, exists in many plants, processed and functional foods. ATB has multiple pharmacological effects, such as antioxidant, lipid-lowering, and hepatoprotective. However, its anti-hepatic fibrosis and mechanisms remain unclearly elucidated. PURPOSE This study explored the effect of ATB against the hepatic fibrosis and its regulation of hepatic microenvironment by regulating hepatic stellate cells-macrophage crosstalk. METHOD Thioacetamide (TAA) was intraperitoneal injected to establish hepatic fibrosis mice, and treated with ATB or curcumin by gavage, respectively. Hepatic stellate cells (HSCs) were stimulated with TGF-β or conditioned medium (CM) from LPS-induced THP-1, then cultured with ATB, PXR agonist or antagonist. RESULTS In TAA-induced mice, ATB improved histopathological changes, serum transaminases increase; alleviated extracellular matrix (ECM) deposition, epithelial-mesenchymal transformation (EMT), inflammatory infiltration, PTEN induced kinase 1 (PINK1)/Parkin-mediated mitophagy and activated pregnane X receptor (PXR) expression. In vitro, ATB significantly reduced ECM, inflammatory cytokines release, mitophagy, EMT, and activated PXR expression. ATB could increase PXR and decrease PINK1/Parkin, functioning as a PXR agonist. PXR deficiency in LX-2 could degrade the regulation of ATB on ECM, inflammation, EMT, and mitophagy. CM from LPS-induced THP-1 activated LX-2 and resulted in PXR decreasing, while ATB could regulate the crosstalk between HSCs and macrophages. Deficiency of PXR, whether in LX-2 or in macrophages, all weakened the inhibitory effect of ATB on α-SMA, EMT, inflammatory cytokines, and PINK1/Parkin signaling. CONCLUSION ATB ameliorated hepatic fibrosis by inhibiting HSCs activation, inflammation and EMT through PXR-mediated PINK1/Parkin signaling. Especially, ATB targeted the hepatic microenvironment between hepatic stellate cells and macrophages, which might be a promising strategy for the treatment of hepatic fibrosis.
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Affiliation(s)
- Jia-Yi Dou
- Key Laboratory for Traditional Chinese Korean Medicine Research (State Ethnic Affairs), College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Mei-Jie Zhou
- Key Laboratory for Traditional Chinese Korean Medicine Research (State Ethnic Affairs), College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Mei-Yan Xuan
- School of Pharmaceutical Sciences, Josai University, Sakado, Saitama, Japan
| | - Jia Guo
- Key Laboratory for Traditional Chinese Korean Medicine Research (State Ethnic Affairs), College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Sai-Hu Liu
- Key Laboratory for Traditional Chinese Korean Medicine Research (State Ethnic Affairs), College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Li-Hua Lian
- Key Laboratory for Traditional Chinese Korean Medicine Research (State Ethnic Affairs), College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Zhen-Yu Cui
- Key Laboratory for Traditional Chinese Korean Medicine Research (State Ethnic Affairs), College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China.
| | - Ji-Xing Nan
- Key Laboratory for Traditional Chinese Korean Medicine Research (State Ethnic Affairs), College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China.
| | - Yan-Ling Wu
- Key Laboratory for Traditional Chinese Korean Medicine Research (State Ethnic Affairs), College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China.
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Thomaz MDL, Vieira CP, Caris JA, Marques MP, Rocha A, Paz TA, Rezende REF, Lanchote VL. Liver Fibrosis Stages Affect Organic Cation Transporter 1/2 Activities in Hepatitis C Virus-Infected Patients. Pharmaceuticals (Basel) 2024; 17:865. [PMID: 39065716 PMCID: PMC11280093 DOI: 10.3390/ph17070865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 06/25/2024] [Accepted: 06/28/2024] [Indexed: 07/28/2024] Open
Abstract
This study aims to evaluate the impact of liver fibrosis stages of chronic infection with hepatitis C virus (HCV) on the in vivo activity of organic cation transporters (hepatic OCT1 and renal OCT2) using metformin (MET) as a probe drug. Participants allocated in Group 1 (n = 15, mild to moderate liver fibrosis) or 2 (n = 13, advanced liver fibrosis and cirrhosis) received a single MET 50 mg oral dose before direct-acting antiviral (DAA) drug treatment (Phase 1) and 30 days after achieving sustained virologic response (Phase 2). OCT1/2 activity (MET AUC0-24) was found to be reduced by 25% when comparing the two groups in Phase 2 (ratio 0.75 (0.61-0.93), p < 0.05) but not in Phase 1 (ratio 0.81 (0.66-0.98), p > 0.05). When Phases 1 and 2 were compared, no changes were detected in both Groups 1 (ratio 1.10 (0.97-1.24), p > 0.05) and 2 (ratio 1.03 (0.94-1.12), p > 0.05). So, this study shows a reduction of approximately 25% in the in vivo activity of OCT1/2 in participants with advanced liver fibrosis and cirrhosis after achieving sustained virologic response and highlights that OCT1/2 in vivo activity depends on the liver fibrosis stage of chronic HCV infection.
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Affiliation(s)
- Matheus De Lucca Thomaz
- Department of Clinical Analysis, Food Science and Toxicology, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-903, Brazil; (M.D.L.T.); (C.P.V.); (J.A.C.); (M.P.M.); (A.R.); (T.A.P.)
| | - Carolina Pinto Vieira
- Department of Clinical Analysis, Food Science and Toxicology, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-903, Brazil; (M.D.L.T.); (C.P.V.); (J.A.C.); (M.P.M.); (A.R.); (T.A.P.)
| | - Juciene Aparecida Caris
- Department of Clinical Analysis, Food Science and Toxicology, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-903, Brazil; (M.D.L.T.); (C.P.V.); (J.A.C.); (M.P.M.); (A.R.); (T.A.P.)
| | - Maria Paula Marques
- Department of Clinical Analysis, Food Science and Toxicology, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-903, Brazil; (M.D.L.T.); (C.P.V.); (J.A.C.); (M.P.M.); (A.R.); (T.A.P.)
| | - Adriana Rocha
- Department of Clinical Analysis, Food Science and Toxicology, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-903, Brazil; (M.D.L.T.); (C.P.V.); (J.A.C.); (M.P.M.); (A.R.); (T.A.P.)
| | - Tiago Antunes Paz
- Department of Clinical Analysis, Food Science and Toxicology, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-903, Brazil; (M.D.L.T.); (C.P.V.); (J.A.C.); (M.P.M.); (A.R.); (T.A.P.)
| | - Rosamar Eulira Fontes Rezende
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto 14049-900, Brazil;
- Reference Center, Hepatitis Outpatient Clinic, Municipal Health Secretary, Ribeirão Preto 14049-900, Brazil
| | - Vera Lucia Lanchote
- Department of Clinical Analysis, Food Science and Toxicology, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-903, Brazil; (M.D.L.T.); (C.P.V.); (J.A.C.); (M.P.M.); (A.R.); (T.A.P.)
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Shi J, Wang X, Qi W, Wang S, Fu Y, Zhang Y, Zhang Q, Han L, Xu Y, Duan H, Liu J, Cong X, Zhou C, Zhao P, Wang J. Association between NTCP hepatic expression and inflammation/fibrosis as well as gender-specific differences in chronic HBV-infected patients. J Med Virol 2024; 96:e29428. [PMID: 38258306 DOI: 10.1002/jmv.29428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 01/09/2024] [Accepted: 01/14/2024] [Indexed: 01/24/2024]
Abstract
To investigate the relationship between the expression of hepatitis B virus (HBV) functional receptor sodium taurocholate cotransporting polypeptide (NTCP) with disease progression and gender-specific differences in chronic HBV-infected patients. Liver samples were collected from chronic HBV-infected patients who underwent percutaneous liver biopsy or liver surgery. HBV DNA levels and the mRNA and protein expression levels of NTCP in liver tissues were determined. The relationship between NTCP expression and HBV DNA levels, inflammatory activity, fibrosis, and gender-specific differences were analyzed. A total of 94 chronic HBV-infected patients were included. Compared with patients with a METAVIR score of A0-1 or F0-1, patients with score of A2 or F2/F3 had a relatively higher level of NTCP expression. NTCP levels were positively correlated with HBV DNA levels. The inflammatory activity scores and fibrosis scores of women <50 years were significantly lower than those of women ≥50 years and age-matched males. In patients with score A0-2 or F0-3, women <50 years have lower NTCP expression level compared to women ≥50 years and age-matched males. NTCP can promote the disease progression by affecting the viral load of HBV. The NTCP expression difference may be why male and postmenopausal women are more prone to disease progression than reproductive women.
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Affiliation(s)
- Jingyi Shi
- Department of Digestive, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Xu Wang
- Department of Digestive, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Wenqian Qi
- Department of Digestive, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Song Wang
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Yao Fu
- Department of Critical Care Medicine, The First Hospital of Jilin University, Changchun, China
| | - Yonggui Zhang
- Department of Digestive, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Qian Zhang
- Department of Digestive, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Liang Han
- Department of Pathology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yanhui Xu
- Department of Gastroenterology and Hepatology, People's Hospital of Zhengzhou University and Henan Provincial People's Hospital, Zhengzhou, China
| | - Honglei Duan
- Department of Digestive, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Jia Liu
- Department of Digestive, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Xianling Cong
- Department of Biobank, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Changyu Zhou
- Department of Digestive, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Ping Zhao
- Department of Digestive, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Jiangbin Wang
- Department of Digestive, China-Japan Union Hospital of Jilin University, Changchun, China
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Lan H, Zhang Y, Fan M, Wu B, Wang C. Pregnane X receptor as a therapeutic target for cholestatic liver injury. Drug Metab Rev 2023; 55:371-387. [PMID: 37593784 DOI: 10.1080/03602532.2023.2248680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 08/02/2023] [Indexed: 08/19/2023]
Abstract
Cholestatic liver injury (CLI) is caused by toxic bile acids (BAs) accumulation in the liver and can lead to inflammation and liver fibrosis. The mechanisms underlying CLI development remain unclear, and this disease has no effective cure. However, regulating BA synthesis and homeostasis represents a promising therapeutic strategy for CLI treatment. Pregnane X receptor (PXR) plays an essential role in the metabolism of endobiotics and xenobiotics via the transcription of metabolic enzymes and transporters, which can ultimately modulate BA homeostasis and exert anticholestatic effects. Furthermore, recent studies have demonstrated that PXR exhibits antifibrotic and anti-inflammatory properties, providing novel insights into treating CLI. Meanwhile, several drugs have been identified as PXR agonists that improve CLI. Nevertheless, the precise role of PXR in CLI still needs to be fully understood. This review summarizes how PXR improves CLI by ameliorating cholestasis, inhibiting inflammation, and reducing fibrosis and discusses the progress of promising PXR agonists for treating CLI.
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Affiliation(s)
- Huan Lan
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, P.R. China
| | - Ying Zhang
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, P.R. China
| | - Minqi Fan
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, P.R. China
| | - Bingxin Wu
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, P.R. China
| | - Caiyan Wang
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, P.R. China
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Ming WH, Luan ZL, Yao Y, Liu HC, Hu SY, Du CX, Zhang C, Zhao YH, Huang YZ, Sun XW, Qiao RF, Xu H, Guan YF, Zhang XY. Pregnane X receptor activation alleviates renal fibrosis in mice via interacting with p53 and inhibiting the Wnt7a/β-catenin signaling. Acta Pharmacol Sin 2023; 44:2075-2090. [PMID: 37344564 PMCID: PMC10545797 DOI: 10.1038/s41401-023-01113-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Accepted: 05/18/2023] [Indexed: 06/23/2023]
Abstract
Renal fibrosis is a common pathological feature of chronic kidney disease (CKD) with various etiologies, which seriously affects the structure and function of the kidney. Pregnane X receptor (PXR) is a member of the nuclear receptor superfamily and plays a critical role in regulating the genes related to xenobiotic and endobiotic metabolism in mammals. Previous studies show that PXR is expressed in the kidney and has protective effect against acute kidney injury (AKI). In this study, we investigated the role of PXR in CKD. Adenine diet-induced CKD (AD) model was established in wild-type and PXR humanized (hPXR) mice, respectively, which were treated with pregnenolone-16α-carbonitrile (PCN, 50 mg/kg, twice a week for 4 weeks) or rifampicin (RIF, 10 mg·kg-1·d-1, for 4 weeks). We showed that both PCN and RIF, which activated mouse and human PXR, respectively, improved renal function and attenuated renal fibrosis in the two types of AD mice. In addition, PCN treatment also alleviated renal fibrosis in unilateral ureter obstruction (UUO) mice. On the contrary, PXR gene deficiency exacerbated renal dysfunction and fibrosis in both adenine- and UUO-induced CKD mice. We found that PCN treatment suppressed the expression of the profibrotic Wnt7a and β-catenin in AD mice and in cultured mouse renal tubular epithelial cells treated with TGFβ1 in vitro. We demonstrated that PXR was colocalized and interacted with p53 in the nuclei of tubular epithelial cells. Overexpression of p53 increased the expression of Wnt7a, β-catenin and its downstream gene fibronectin. We further revealed that p53 bound to the promoter of Wnt7a gene to increase its transcription and β-catenin activation, leading to increased expression of the downstream profibrotic genes, which was inhibited by PXR. Taken together, PXR activation alleviates renal fibrosis in mice via interacting with p53 and inhibiting the Wnt7a/β-catenin signaling pathway.
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Affiliation(s)
- Wen-Hua Ming
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China
- Health Science Center, East China Normal University, Shanghai, 200241, China
| | - Zhi-Lin Luan
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
- Dalian Key Laboratory for Nuclear Receptors in Major Metabolic Diseases, Dalian, 116044, China
| | - Yao Yao
- Department of nephrology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226006, China
| | - Hang-Chi Liu
- Health Science Center, East China Normal University, Shanghai, 200241, China
| | - Shu-Yuan Hu
- Department of nephrology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226006, China
| | - Chun-Xiu Du
- Division of Nephrology, Wuhu Hospital, East China Normal University, Wuhu, 241100, China
| | - Cong Zhang
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Yi-Hang Zhao
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Ying-Zhi Huang
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Xiao-Wan Sun
- Health Science Center, East China Normal University, Shanghai, 200241, China
| | - Rong-Fang Qiao
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Hu Xu
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
- Dalian Key Laboratory for Nuclear Receptors in Major Metabolic Diseases, Dalian, 116044, China
| | - You-Fei Guan
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China.
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China.
- Dalian Key Laboratory for Nuclear Receptors in Major Metabolic Diseases, Dalian, 116044, China.
| | - Xiao-Yan Zhang
- Health Science Center, East China Normal University, Shanghai, 200241, China.
- Division of Nephrology, Wuhu Hospital, East China Normal University, Wuhu, 241100, China.
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Obradovic B, Roberts O, Owen A, Milosevic I, Milic N, Ranin J, Dragovic G. Expression of CYP2B6 Enzyme in Human Liver Tissue of HIV and HCV Patients. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1207. [PMID: 37512019 PMCID: PMC10385124 DOI: 10.3390/medicina59071207] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 06/15/2023] [Accepted: 06/21/2023] [Indexed: 07/30/2023]
Abstract
Background and Objectives: Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections present significant public health challenges worldwide. The management of these infections is complicated by the need for antiviral and antiretroviral therapies, which are influenced by drug metabolism mediated by metabolic enzymes and transporters. This study focuses on the gene expression of CYP2B6, CYP3A4, and ABCB1 transporters in patients with HIV, HCV, and HIV/HCV co-infection, aiming to assess their potential association with the choice of therapy, patohistological and clinical parameters of liver damage such as the stage of liver fibrosis, serum levels of ALT and AST, as well as the grade of liver inflammation and other available biochemical parameters. Materials and Methods: The study included 54 patients who underwent liver biopsy, divided into HIV-infected, HCV-infected, and co-infected groups. The mRNA levels of CYP2B6, CYP3A4, and ABCB1 was quantified and compared between the groups, along with the analysis of liver fibrosis and inflammation levels. Results: The results indicated a significant increase in CYP2B6 mRNA levels in co-infected patients, a significant association with the presence of HIV infection with an increase in CYP3A4 mRNA levels. A trend towards downregulation of ABCB1 expression was observed in patients using lamivudine. Conclusions: This study provides insight into gene expression of CYP2B6 CYP3A4, and ABCB1 in HIV, HCV, and HIV/HCV co-infected patients. The absence of correlation with liver damage, inflammation, and specific treatment interventions emphasises the need for additional research to elucidate the complex interplay between gene expression, viral co-infection, liver pathology, and therapeutic responses in these particular patients population.
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Affiliation(s)
- Bozana Obradovic
- University of Belgrade, Faculty of Medicine, Department of Pharmacology, Clinical Pharmacology and Toxicology, 11000 Belgrade, Serbia
| | - Owain Roberts
- University of Buckingham Medical School, Faculty of Medicine and Health Sciences, University of Buckingham, Buckingham MK18 1EG, UK
| | - Andrew Owen
- Centre of Excellence in Long-Acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3BX, UK
| | - Ivana Milosevic
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
- Clinic of Infectious and Tropical Diseases, Clinical Centre of Serbia, 11000 Belgrade, Serbia
| | - Natasa Milic
- University of Belgrade, Faculty of Medicine, Department of Medical Statistics & Informatics, 11000 Belgrade, Serbia
| | - Jovan Ranin
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
- Clinic of Infectious and Tropical Diseases, Clinical Centre of Serbia, 11000 Belgrade, Serbia
| | - Gordana Dragovic
- University of Belgrade, Faculty of Medicine, Department of Pharmacology, Clinical Pharmacology and Toxicology, 11000 Belgrade, Serbia
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Patil NY, Friedman JE, Joshi AD. Role of Hepatic Aryl Hydrocarbon Receptor in Non-Alcoholic Fatty Liver Disease. RECEPTORS (BASEL, SWITZERLAND) 2023; 2:1-15. [PMID: 37284280 PMCID: PMC10240927 DOI: 10.3390/receptors2010001] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Numerous nuclear receptors including farnesoid X receptor, liver X receptor, peroxisome proliferator-activated receptors, pregnane X receptor, hepatic nuclear factors have been extensively studied within the context of non-alcoholic fatty liver disease (NAFLD). Following the first description of the Aryl hydrocarbon Receptor (AhR) in the 1970s and decades of research which unveiled its role in toxicity and pathophysiological processes, the functional significance of AhR in NAFLD has not been completely decoded. Recently, multiple research groups have utilized a plethora of in vitro and in vivo models that mimic NAFLD pathology to investigate the functional significance of AhR in fatty liver disease. This review provides a comprehensive account of studies describing both the beneficial and possible detrimental role of AhR in NAFLD. A plausible reconciliation for the paradox indicating AhR as a 'double-edged sword' in NAFLD is discussed. Finally, understanding AhR ligands and their signaling in NAFLD will facilitate us to probe AhR as a potential drug target to design innovative therapeutics against NAFLD in the near future.
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Affiliation(s)
- Nikhil Y. Patil
- Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
| | - Jacob E. Friedman
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
| | - Aditya D. Joshi
- Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
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Bae SH, Choi HG, Park SY, Chang SY, Kim H, Kim SH. Effects of Isosakuranetin on Pharmacokinetic Changes of Tofacitinib in Rats with N-Dimethylnitrosamine-Induced Liver Cirrhosis. Pharmaceutics 2022; 14:pharmaceutics14122684. [PMID: 36559177 PMCID: PMC9783783 DOI: 10.3390/pharmaceutics14122684] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/07/2022] [Accepted: 11/29/2022] [Indexed: 12/05/2022] Open
Abstract
Tofacitinib, a Janus kinase 1 and 3 inhibitor, is used to treat rheumatoid arthritis. It is mainly metabolized by the cytochromes p450 (CYP) 3A1/2 and CYP2C11 in the liver. Chronic inflammation eventually leads to cirrhosis in patients with rheumatoid arthritis. Isosakuranetin (ISN), a component of Citrus aurantium L., has hepatoprotective effects in rats. This study was performed to determine the effects of ISN on the pharmacokinetics of tofacitinib in rats with N-dimethylnitrosamine-induced liver cirrhosis (LC). After intravenous administration of 10 mg/kg tofacitinib to control (CON), LC, and LC treated with ISN (LC-ISN) rats, the total area under the plasma concentration-time curves (AUC) from time zero to infinity increased by 158% in LC rats compared to those in CON rats; however, the AUC of LC-ISN rats decreased by 35.1% compared to that of LC rat. Similar patterns of AUC changes were observed in the LC and LC-ISN rats after oral administration of 20 mg/kg tofacitinib. These results can be attributed to decreased non-renal clearance (CLNR) and intestinal intrinsic clearance (CLint) in the LC rats and increased intestinal and hepatic CLint in the LC-ISN rats. Our findings imply that ISN treatment in LC rats restored the decrease in either CLNR or CLint, or both, through increased hepatic and intestinal expression of CYP3A1/2 and CYP2C11, which is regulated by the induction of pregnane X receptor (PXR) and constitutive androstane receptor (CAR).
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Affiliation(s)
- Sung Hun Bae
- College of Pharmacy and Research Institute of Pharmaceutical Science and Technology, Ajou University, 206 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea
| | - Hyeon Gyeom Choi
- College of Pharmacy and Research Institute of Pharmaceutical Science and Technology, Ajou University, 206 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea
| | - So Yeon Park
- Department of Biohealth Regulatory Science, Graduate School of Ajou University, 206 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea
| | - Sun-Young Chang
- College of Pharmacy and Research Institute of Pharmaceutical Science and Technology, Ajou University, 206 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea
- Department of Biohealth Regulatory Science, Graduate School of Ajou University, 206 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea
| | - Hyoungsu Kim
- College of Pharmacy and Research Institute of Pharmaceutical Science and Technology, Ajou University, 206 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea
| | - So Hee Kim
- College of Pharmacy and Research Institute of Pharmaceutical Science and Technology, Ajou University, 206 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea
- Department of Biohealth Regulatory Science, Graduate School of Ajou University, 206 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea
- Correspondence: ; Tel.: +82-31-219-3451
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Portal hypertension may influence the registration of hypointensity of small hepatocellular carcinoma in the hepatobiliary phase in gadoxetic acid MR. Radiol Oncol 2022; 56:292-302. [PMID: 35776837 PMCID: PMC9400438 DOI: 10.2478/raon-2022-0024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 04/24/2022] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND The aim of the study was to analyze the association between the liver uptake of Gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid (Gd-EOB-DTPA) in the hepatobiliary phase (HBP) in cirrhotic patients and the presence of clinically significant portal hypertension (CSPH), and how these features impact on hepatocellular carcinoma (HCC) detection in the HBP. PATIENTS AND METHODS Post-hoc analysis of a prospective cohort of 62 cirrhotic patients with newly US-detected nodule between 1-2 cm (study group). Twenty healthy subjects were used as control group. Qualitative and quantitative analysis of the liver contrast uptake in the HBP assessed by Relative Liver-Enhancement (RLE), Liver-Spleen (LSCR), Liver-Muscle (LMCR), and Liver-Kidney Contrast-Ratio (LKCR), Contrast Enhancement Index (CEI), and Hepatic Uptake (HUI), and biliary excretion, were registered. CSPH was confirmed invasively (HVPG > 10 mmHg) or by indirect parameters. The appearance of HCC at the HBP was analyzed. RESULTS Nineteen patients (30.6%) did not have CSPH. In 41 patients (66.1%) the final diagnosis was HCC. All indices were significantly higher in the control group, indicating a more intense HBP liver signal intensity compared to patients with cirrhosis, even if the comparison was restricted to patients with no CSPH. CSPH was associated to a lower rate of HCC hypointensity in the HBP (51.9% vs. 85.7% without CSPH, p = 0.004). CONCLUSIONS Liver uptake of Gd-EOB-DTPA at the HBP is decreased in cirrhosis even if the liver function is minimally impaired and it falls down significantly in patients with CSPH compromising the recognition of hypointense lesions. This fact may represent a limitation for the detection of small HCC in patients with cirrhosis and CSPH.
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10
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Xia Y, Yan M, Wang P, Hamada K, Yan N, Hao H, Gonzalez FJ, Yan T. Withaferin A in the Treatment of Liver Diseases: Progress and Pharmacokinetic Insights. Drug Metab Dispos 2022; 50:685-693. [PMID: 34903587 PMCID: PMC9132099 DOI: 10.1124/dmd.121.000455] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 12/06/2021] [Indexed: 11/22/2022] Open
Abstract
Withaferin A (WA) is a natural steroidal compound used in Ayurvedic medicine in India and elsewhere. Although WA was used as an anticancer reagent for decades, its role in the treatment of liver diseases has only recently been experimentally explored. Here, the effects of WA in the treatment of liver injury, systematic inflammation, and liver cancer are reviewed, and the toxicity and metabolism of WA as well as pharmacological potentials of other extracts from Withania somnifera (W. somnifera) discussed. The pharmacokinetic behaviors of WA are summarized and pharmacokinetic insights into current progress and future opportunities are highlighted. SIGNIFICANCE STATEMENT: This review outlines the current experimental progress of Withaferin A (WA) hepatoprotective activities and highlights gaps in the field. This work also discusses the pharmacokinetics of WA that can be used to guide future studies for the possible treatment of liver diseases with this compound.
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Affiliation(s)
- Yangliu Xia
- School of Life Science and Medicine, Dalian University of Technology, Panjin, China (Y.X., M.Y.); Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (Y.X., K.H., F.J.G., T.Y.); Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (P.W.); State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (N.Y., H.H.); and Laboratory of Clinical Biochemistry, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan (K.H.)
| | - Mingrui Yan
- School of Life Science and Medicine, Dalian University of Technology, Panjin, China (Y.X., M.Y.); Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (Y.X., K.H., F.J.G., T.Y.); Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (P.W.); State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (N.Y., H.H.); and Laboratory of Clinical Biochemistry, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan (K.H.)
| | - Ping Wang
- School of Life Science and Medicine, Dalian University of Technology, Panjin, China (Y.X., M.Y.); Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (Y.X., K.H., F.J.G., T.Y.); Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (P.W.); State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (N.Y., H.H.); and Laboratory of Clinical Biochemistry, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan (K.H.)
| | - Keisuke Hamada
- School of Life Science and Medicine, Dalian University of Technology, Panjin, China (Y.X., M.Y.); Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (Y.X., K.H., F.J.G., T.Y.); Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (P.W.); State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (N.Y., H.H.); and Laboratory of Clinical Biochemistry, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan (K.H.)
| | - Nana Yan
- School of Life Science and Medicine, Dalian University of Technology, Panjin, China (Y.X., M.Y.); Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (Y.X., K.H., F.J.G., T.Y.); Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (P.W.); State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (N.Y., H.H.); and Laboratory of Clinical Biochemistry, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan (K.H.)
| | - Haiping Hao
- School of Life Science and Medicine, Dalian University of Technology, Panjin, China (Y.X., M.Y.); Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (Y.X., K.H., F.J.G., T.Y.); Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (P.W.); State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (N.Y., H.H.); and Laboratory of Clinical Biochemistry, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan (K.H.)
| | - Frank J Gonzalez
- School of Life Science and Medicine, Dalian University of Technology, Panjin, China (Y.X., M.Y.); Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (Y.X., K.H., F.J.G., T.Y.); Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (P.W.); State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (N.Y., H.H.); and Laboratory of Clinical Biochemistry, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan (K.H.)
| | - Tingting Yan
- School of Life Science and Medicine, Dalian University of Technology, Panjin, China (Y.X., M.Y.); Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (Y.X., K.H., F.J.G., T.Y.); Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (P.W.); State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (N.Y., H.H.); and Laboratory of Clinical Biochemistry, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan (K.H.)
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11
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Sayaf K, Zanotto I, Russo FP, Gabbia D, De Martin S. The Nuclear Receptor PXR in Chronic Liver Disease. Cells 2021; 11:61. [PMID: 35011625 PMCID: PMC8750019 DOI: 10.3390/cells11010061] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 12/21/2021] [Accepted: 12/24/2021] [Indexed: 02/06/2023] Open
Abstract
Pregnane X receptor (PXR), a nuclear receptor known for modulating the transcription of drug metabolizing enzymes and transporters (DMETs), such as cytochrome P450 3A4 and P-glycoprotein, is functionally involved in chronic liver diseases of different etiologies. Furthermore, PXR activity relates to that of other NRs, such as constitutive androstane receptor (CAR), through a crosstalk that in turn orchestrates a complex network of responses. Thus, besides regulating DMETs, PXR signaling is involved in both liver damage progression and repair and in the neoplastic transition to hepatocellular carcinoma. We here summarize the present knowledge about PXR expression and function in chronic liver diseases characterized by different etiologies and clinical outcome, focusing on the molecular pathways involved in PXR activity. Although many molecular details of these finely tuned networks still need to be fully understood, we conclude that PXR and its modulation could represent a promising pharmacological target for the identification of novel therapeutical approaches to chronic liver diseases.
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Affiliation(s)
- Katia Sayaf
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35121 Padova, Italy; (K.S.); (F.P.R.)
| | - Ilaria Zanotto
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35121 Padova, Italy; (I.Z.); (S.D.M.)
| | - Francesco Paolo Russo
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35121 Padova, Italy; (K.S.); (F.P.R.)
| | - Daniela Gabbia
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35121 Padova, Italy; (I.Z.); (S.D.M.)
| | - Sara De Martin
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35121 Padova, Italy; (I.Z.); (S.D.M.)
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12
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Lenoir C, Rollason V, Desmeules JA, Samer CF. Influence of Inflammation on Cytochromes P450 Activity in Adults: A Systematic Review of the Literature. Front Pharmacol 2021; 12:733935. [PMID: 34867341 PMCID: PMC8637893 DOI: 10.3389/fphar.2021.733935] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 10/13/2021] [Indexed: 12/15/2022] Open
Abstract
Background: Available in-vitro and animal studies indicate that inflammation impacts cytochromes P450 (CYP) activity via multiple and complex transcriptional and post-transcriptional mechanisms, depending on the specific CYP isoforms and the nature of inflammation mediators. It is essential to review the current published data on the impact of inflammation on CYP activities in adults to support drug individualization based on comorbidities and diseases in clinical practice. Methods: This systematic review was conducted in PubMed through 7th January 2021 looking for articles that investigated the consequences of inflammation on CYP activities in adults. Information on the source of inflammation, victim drugs (and CYPs involved), effect of disease-drug interaction, number of subjects, and study design were extracted. Results: The search strategy identified 218 studies and case reports that met our inclusion criteria. These articles were divided into fourteen different sources of inflammation (such as infection, autoimmune diseases, cancer, therapies with immunomodulator…). The impact of inflammation on CYP activities appeared to be isoform-specific and dependent on the nature and severity of the underlying disease causing the inflammation. Some of these drug-disease interactions had a significant influence on drug pharmacokinetic parameters and on clinical management. For example, clozapine levels doubled with signs of toxicity during infections and the concentration ratio between clopidogrel's active metabolite and clopidogrel is 48-fold lower in critically ill patients. Infection and CYP3A were the most cited perpetrator of inflammation and the most studied CYP, respectively. Moreover, some data suggest that resolution of inflammation results in a return to baseline CYP activities. Conclusion: Convincing evidence shows that inflammation is a major factor to be taken into account in drug development and in clinical practice to avoid any efficacy or safety issues because inflammation modulates CYP activities and thus drug pharmacokinetics. The impact is different depending on the CYP isoform and the inflammatory disease considered. Moreover, resolution of inflammation appears to result in a normalization of CYP activity. However, some results are still equivocal and further investigations are thus needed.
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Affiliation(s)
- Camille Lenoir
- Division of Clinical Pharmacology and Toxicology, Department of Anesthesiology, Pharmacology, Intensive Care, and Emergency Medicine, Geneva University Hospitals, Geneva, Switzerland.,Institute of Pharmaceutical Sciences of Western Switzerland (ISPSO), School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland
| | - Victoria Rollason
- Division of Clinical Pharmacology and Toxicology, Department of Anesthesiology, Pharmacology, Intensive Care, and Emergency Medicine, Geneva University Hospitals, Geneva, Switzerland.,Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Jules A Desmeules
- Division of Clinical Pharmacology and Toxicology, Department of Anesthesiology, Pharmacology, Intensive Care, and Emergency Medicine, Geneva University Hospitals, Geneva, Switzerland.,Institute of Pharmaceutical Sciences of Western Switzerland (ISPSO), School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.,Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Caroline F Samer
- Division of Clinical Pharmacology and Toxicology, Department of Anesthesiology, Pharmacology, Intensive Care, and Emergency Medicine, Geneva University Hospitals, Geneva, Switzerland.,Faculty of Medicine, University of Geneva, Geneva, Switzerland
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13
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Pippa LF, Vieira CP, Caris JA, Rocha A, Garcia CP, Rezende REF, Lanchote VL. Clinical treatment for hepatitis C reverses CYP2C19 inhibition. Br J Clin Pharmacol 2021; 87:4013-4019. [PMID: 33738827 DOI: 10.1111/bcp.14829] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 02/19/2021] [Accepted: 02/22/2021] [Indexed: 12/15/2022] Open
Abstract
AIMS Infection by the hepatitis C virus (HCV) generates inflammatory response selectively modulating cytochrome P450 protein (CYP) activities. This study assessed the effect of chronic hepatitis C on CYP2C19 activity in patients with HCV. METHODS Patients with HCV infection (n = 23) at different fibrosis stages were allocated into groups 1 (F0/F1 and F2, mild to moderate fibrosis) and 2 (F3 and F4, advanced fibrosis stages). Phase 1 was conducted before the treatment with direct-acting antivirals (DAAs) and phase 2 after the sustained virological response. Participants were administered 2 mg of a single oral dose of omeprazole (OME) as probe drug in both phases. Metabolic ratios (MRs) (plasma samples collected at 4 h after OME administration) were calculated by dividing plasma concentrations of 5-hydroxyomeprazole by OME. RESULTS The MRs for group 1 were 0.45 (0.34-0.60, 90% confidence interval) and 0.69 (0.50-0.96) for phases 1 and 2, respectively, while the MRs for group 2 were 0.25 (0.21-0.31) and 0.41 (0.30-0.56) for phases 1 and 2, respectively. MRs were different (P < .05) between phases 1 and 2 for both groups, as well as between groups 1 and 2 in phase 1, but not in phase 2 (P > .05). CONCLUSIONS Both groups presented different MRs before and after treatment with DAAs, evidencing that CYP2C19 inhibition during inflammation was at least partially reversed after DAA treatment. Groups 1 and 2 were also found to be different in phase 1 but not phase 2, showing that CYP2C19 metabolic activity does not differ between groups after DAA treatment.
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Affiliation(s)
- Leandro Francisco Pippa
- Department of Clinical Analyses, Toxicology and Food Science, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Carolina Pinto Vieira
- Department of Clinical Analyses, Toxicology and Food Science, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Juciene Aparecida Caris
- Department of Neurosciences and Behavioural Sciences, School of Medicine of Ribeirão Preto, University of São Paulo, Brazil
| | - Adriana Rocha
- Department of Clinical Analyses, Toxicology and Food Science, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Camile Prates Garcia
- Department of Internal Medicine, Division of Gastroenterology, School of Medicine of Ribeirão Preto, University of São Paulo, Brazil
| | - Rosamar Eulira Fontes Rezende
- Department of Internal Medicine, Division of Gastroenterology, School of Medicine of Ribeirão Preto, University of São Paulo, Brazil.,Reference Centre, Hepatitis Outpatient Clinic, Municipal Health Secretary, Ribeirão Preto, São Paulo, Brazil
| | - Vera Lucia Lanchote
- Department of Clinical Analyses, Toxicology and Food Science, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
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14
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Zhou S, Zeng S, Shu Y. Drug-Drug Interactions at Organic Cation Transporter 1. Front Pharmacol 2021; 12:628705. [PMID: 33679412 PMCID: PMC7925875 DOI: 10.3389/fphar.2021.628705] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 01/13/2021] [Indexed: 12/19/2022] Open
Abstract
The interaction between drugs and various transporters is one of the decisive factors that affect the pharmacokinetics and pharmacodynamics of drugs. The organic cation transporter 1 (OCT1) is a member of the Solute Carrier 22A (SLC22A) family that plays a vital role in the membrane transport of organic cations including endogenous substances and xenobiotics. This article mainly discusses the drug-drug interactions (DDIs) mediated by OCT1 and their clinical significance.
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Affiliation(s)
- Shiwei Zhou
- Key Laboratory of Oral Medicine, School and Hospital of Stomatology, Guangzhou Medical University, Guangzhou, China.,Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, Baltimore, MD, United States.,Department of Thyroid Surgery, The Second Xiangya Hospital, Central South University, Hunan, China
| | - Sujuan Zeng
- Key Laboratory of Oral Medicine, School and Hospital of Stomatology, Guangzhou Medical University, Guangzhou, China
| | - Yan Shu
- Key Laboratory of Oral Medicine, School and Hospital of Stomatology, Guangzhou Medical University, Guangzhou, China.,Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, Baltimore, MD, United States
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15
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Drug-Drug Interactions Involving Intestinal and Hepatic CYP1A Enzymes. Pharmaceutics 2020; 12:pharmaceutics12121201. [PMID: 33322313 PMCID: PMC7764576 DOI: 10.3390/pharmaceutics12121201] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 12/02/2020] [Accepted: 12/08/2020] [Indexed: 12/29/2022] Open
Abstract
Cytochrome P450 (CYP) 1A enzymes are considerably expressed in the human intestine and liver and involved in the biotransformation of about 10% of marketed drugs. Despite this doubtless clinical relevance, CYP1A1 and CYP1A2 are still somewhat underestimated in terms of unwanted side effects and drug–drug interactions of their respective substrates. In contrast to this, many frequently prescribed drugs that are subjected to extensive CYP1A-mediated metabolism show a narrow therapeutic index and serious adverse drug reactions. Consequently, those drugs are vulnerable to any kind of inhibition or induction in the expression and function of CYP1A. However, available in vitro data are not necessarily predictive for the occurrence of clinically relevant drug–drug interactions. Thus, this review aims to provide an up-to-date summary on the expression, regulation, function, and drug–drug interactions of CYP1A enzymes in humans.
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16
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Ozawa S, Miura T, Terashima J, Habano W, Ishida S. Recent Progress in Prediction Systems for Drug-induced Liver Injury Using in vitro Cell Culture. Drug Metab Lett 2020; 14:25-40. [PMID: 33267768 DOI: 10.2174/1872312814666201202112610] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 11/26/2020] [Accepted: 11/03/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND In order to avoid drug-induced liver injury (DILI), in vitro assays, which enable the assessment of both metabolic activation and immune reaction processes that ultimately result in DILI, are needed. OBJECTIVE In this study, the recent progress in the application of in vitro assays using cell culture systems is reviewed for potential DILI-causing drugs/xenobiotics and a mechanistic study on DILI, as well as for the limitations of in vitro cell culture systems for DILI research. METHODS Information related to DILI was collected through a literature search of the PubMed database. RESULTS The initial biological event for the onset of DILI is the formation of cellular protein adducts after drugs have been metabolically activated by drug metabolizing enzymes. The damaged peptides derived from protein adducts lead to the activation of CD4+ helper T lymphocytes and recognition by CD8+ cytotoxic T lymphocytes, which destroy hepatocytes through immunological reactions. Because DILI is a major cause of drug attrition and drug withdrawal, numerous in vitro systems consisting of hepatocytes and immune/inflammatory cells, or spheroids of human primary hepatocytes containing non-parenchymal cells have been developed. These cellular-based systems have identified DILIinducing drugs with approximately 50% sensitivity and 90% specificity. CONCLUSION Different co-culture systems consisting of human hepatocyte-derived cells and other immune/inflammatory cells have enabled the identification of DILI-causing drugs and of the actual mechanisms of action.
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Affiliation(s)
- Shogo Ozawa
- Department of Clinical Pharmaceutical Sciences, Division of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Yahaba. Japan
| | - Toshitaka Miura
- Department of Clinical Pharmaceutical Sciences, Division of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Yahaba. Japan
| | - Jun Terashima
- Department of Clinical Pharmaceutical Sciences, Division of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Yahaba. Japan
| | - Wataru Habano
- Department of Clinical Pharmaceutical Sciences, Division of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Yahaba. Japan
| | - Seiichi Ishida
- Department of Pharmacology, National Institute of Health Sciences, Kawasaki. Japan
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17
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Daujat-Chavanieu M, Gerbal-Chaloin S. Regulation of CAR and PXR Expression in Health and Disease. Cells 2020; 9:E2395. [PMID: 33142929 PMCID: PMC7692647 DOI: 10.3390/cells9112395] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 10/22/2020] [Accepted: 10/28/2020] [Indexed: 12/12/2022] Open
Abstract
Pregnane X receptor (PXR, NR1I2) and constitutive androstane receptor (CAR, NR1I3) are members of the nuclear receptor superfamily that mainly act as ligand-activated transcription factors. Their functions have long been associated with the regulation of drug metabolism and disposition, and it is now well established that they are implicated in physiological and pathological conditions. Considerable efforts have been made to understand the regulation of their activity by their cognate ligand; however, additional regulatory mechanisms, among which the regulation of their expression, modulate their pleiotropic effects. This review summarizes the current knowledge on CAR and PXR expression during development and adult life; tissue distribution; spatial, temporal, and metabolic regulations; as well as in pathological situations, including chronic diseases and cancers. The expression of CAR and PXR is modulated by complex regulatory mechanisms that involve the interplay of transcription factors and also post-transcriptional and epigenetic modifications. Moreover, many environmental stimuli affect CAR and PXR expression through mechanisms that have not been elucidated.
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Affiliation(s)
| | - Sabine Gerbal-Chaloin
- IRMB, University of Montpellier, INSERM, CHU Montpellier, 34295 Montpellier, France;
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18
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Hu J, Tian J, Zhang F, Wang H, Yin J. Pxr- and Nrf2- mediated induction of ABC transporters by heavy metal ions in zebrafish embryos. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2019; 255:113329. [PMID: 31600704 DOI: 10.1016/j.envpol.2019.113329] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 08/27/2019] [Accepted: 09/29/2019] [Indexed: 05/13/2023]
Abstract
Transcription factors including pregnane X receptor (Pxr) and nuclear factor-erythroid 2-related factor-2 (Nrf2) are important modulators of Adenosine triphosphate-binding cassette (ABC) transporters in mammalian cells. However, whether such modulation is conserved in zebrafish embryos remains largely unknown. In this manuscript, pxr- and nrf2-deficient models were constructed with CRISPR/Cas9 system, to evaluate the individual function of Pxr and Nrf2 in the regulation of ABC transporters and detoxification of heavy metal ions like Cd2+ and Ag+. As a result, both Cd2+ and Ag+ conferred extensive interactions with ABC transporters in wild type (WT) embryos: their accumulation and toxicity were affected by the activity of ABC transporters, and they significantly induced the mRNA expressions of ABC transporters. These induction effects were reduced by the mutation of pxr and nrf2, but elevations in the basal expression of ABC transporters compensated for the loss of their inducibility. This could be an explanation for remaining transporter function in both mutant models as well as the unaltered toxicity of metal ions in pxr-deficient embryos. However, mutation of nrf2 disrupted the production of glutathione (GSH), resulting in the enhanced toxicity of Cd2+/Ag+ in zebrafish embryos. In addition, elevated expressions of other transcription factors like aryl hydrocarbon receptor (ahr) 1b, peroxisome proliferator-activated receptor (ppar)-β, and nrf2 were found in pxr-deficient models without any treatment, while enhanced induction of ahr1b, ppar-β and pxr could only be seen in nrf2-deficient embryos after the treatment of metal ions, indicating different compensation phenomena for the absence of transcription factors. After all, pxr-deficient and nrf2-deficient zebrafish embryos are useful tools in the functional investigation of Pxr and Nrf2 in the early life stages of aquatic organisms. However, the compensatory mechanisms should be taken into consideration when interpreting the results and need in-depth investigations.
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Affiliation(s)
- Jia Hu
- School of Biology & Basic Medical Sciences, Medical College, Soochow University, Suzhou, Jiangsu 215123, PR China
| | - Jingjing Tian
- CAS Key Lab of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, Jiangsu 215163, PR China; Academy for Engineering & Technology, Fudan University, Shanghai 200433, PR China
| | - Feng Zhang
- Suzhou GCL Photovoltaic Technology Co., Ltd, Suzhou, Jiangsu 215163, PR China
| | - Han Wang
- School of Biology & Basic Medical Sciences, Medical College, Soochow University, Suzhou, Jiangsu 215123, PR China
| | - Jian Yin
- CAS Key Lab of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, Jiangsu 215163, PR China; Shandong Guo Ke Medical Technology Development Co., Ltd, PR China.
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19
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Vollmar J, Kim YO, Marquardt JU, Becker D, Galle PR, Schuppan D, Zimmermann T. Deletion of organic cation transporter Oct3 promotes hepatic fibrosis via upregulation of TGFβ. Am J Physiol Gastrointest Liver Physiol 2019; 317:G195-G202. [PMID: 31241979 DOI: 10.1152/ajpgi.00088.2019] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Organic cation transporters (OCT) are responsible for the intracellular uptake and detoxification of a broad spectrum of endogenous and exogenous substrates. OCTs are downregulated in cholestasis, fibrosis, and hepatocellular carcinoma, but the underlying molecular mechanisms and downstream effects of OCT deletion are unknown. Oct3-knockout (Oct3-/-; FVB.Slc22a3tm10pb) and wild-type (WT; FVB) mice were subject to escalating doses of carbon tetrachloride (CCl4) or thioacetamide (TAA) for 6 wk to induce advanced parenchymal liver fibrosis. Secondary biliary fibrosis was generated by bile duct ligation. Liver fibrosis was assessed by hydroxyproline determination, quantitative Sirius red morphometry, and quantitative real-time PCR for fibrosis and inflammation-related genes. Ductular reaction was assessed by bile duct count per field of view in hematoxylin and eosin staining. General gene expression analyses were performed in liver tissue from untreated Oct3-/- and WT mice. Finally, primary murine hepatocytes were treated with the nonselective OCT inhibitor quinine, and transforming growth factor-β1 (Tgfβ1) protein expression was quantified by quantitative real-time PCR and Western blot. Oct3-/- mice developed significantly more fibrosis after bile duct ligation and CCl4 treatment compared with WT mice. Ductular reaction was enhanced in the long-term model. Concomitantly, Oct1 mRNA expression was downregulated during cholestatic and chemically (TAA and CCl4) induced fibrogenesis. The downregulation of Oct1 mRNA in fibrotic liver tissue reversed within 4 wk after TAA cessation. Gene expression analysis by next-generation sequencing revealed an enrichment of Tgfβ1 target genes in Oct3-/- mice. Tgfβ1 mRNA expression was significantly upregulated after chemically induced fibrosis (P < 0.001) in Oct3-/- compared with WT mice. Accordingly, in primary murine hepatocytes functional inhibition of OCT led to an upregulation of Tgfβ1 mRNA expression. Loss of Oct3 promotes fibrogenesis by affecting Tgfβ-mediated homeostasis in mice with chronic biliary and parenchymal liver damage and fibrosis.NEW & NOTEWORTHY We show for the first time that organic cation transporter 3 (Oct3) is not only downregulated in fibrosis but loss of Oct3 also leads to an upregulation of transforming growth factor-β contributing to fibrosis progression.
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Affiliation(s)
- Johanna Vollmar
- 1st Department of Internal Medicine, Gastroenterology, and Hepatology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany
| | - Yong Ook Kim
- Institute of Translational Immunology, Fibrosis and Metabolism Center, Johannes Gutenberg-University, Mainz, Germany
| | - Jens U Marquardt
- 1st Department of Internal Medicine, Gastroenterology, and Hepatology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany
| | - Diana Becker
- 1st Department of Internal Medicine, Gastroenterology, and Hepatology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany
| | - Peter R Galle
- 1st Department of Internal Medicine, Gastroenterology, and Hepatology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany
| | - Detlef Schuppan
- Institute of Translational Immunology, Fibrosis and Metabolism Center, Johannes Gutenberg-University, Mainz, Germany
| | - Tim Zimmermann
- 1st Department of Internal Medicine, Gastroenterology, and Hepatology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany
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Rigalli JP, Tocchetti GN, Weiss J. Modulation of ABC Transporters by Nuclear Receptors: Physiological, Pathological and Pharmacological Aspects. Curr Med Chem 2019; 26:1079-1112. [DOI: 10.2174/0929867324666170920141707] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 07/24/2017] [Accepted: 08/08/2017] [Indexed: 12/11/2022]
Abstract
ABC transporters are membrane proteins mediating the efflux of endo- and xenobiotics. Transporter expression is not static but instead is subject to a dynamic modulation aiming at responding to changes in the internal environment and thus at maintaining homeostatic conditions. Nuclear receptors are ligand modulated transcription factors that get activated upon changes in the intracellular concentrations of the respective agonists and bind to response elements within the promoter of ABC transporters, thus modulating their expression and, consequently, their activity. This review compiles information about transporter regulation by nuclear receptors classified according to the perpetrator compounds and the biological effects resulting from the regulation. Modulation by hormone receptors is involved in maintaining endocrine homeostasis and may also lead to an altered efflux of other substrates in cases of altered hormonal levels. Xenobiotic receptors play a key role in limiting the accumulation of potentially harmful compounds. In addition, their frequent activation by therapeutic agents makes them common molecular elements mediating drug-drug interactions and cancer multidrug resistance. Finally, lipid and retinoid receptors are usually activated by endogenous molecules, thus sensing metabolic changes and inducing ABC transporters to counteract potential alterations. Furthermore, the axis nuclear receptor-ABC transporter constitutes a promising therapeutic target for the treatment of several disease states like cancer, atherosclerosis and dyslipidemia. In the current work, we summarize the information available on the pharmacological potential of nuclear receptor modulators and discuss their applicability in the clinical practice.
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Affiliation(s)
- Juan Pablo Rigalli
- Department of Clinical Pharmacology and Pharmacoepidemiology. University of Heidelberg. Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Guillermo Nicolás Tocchetti
- Department of Clinical Pharmacology and Pharmacoepidemiology. University of Heidelberg. Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Johanna Weiss
- Department of Clinical Pharmacology and Pharmacoepidemiology. University of Heidelberg. Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
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Zhong Y, Li S, Chen L, Liu Z, Luo X, Xu P, Chen L. In Vivo Toxicity of Solasonine and Its Effects on cyp450 Family Gene Expression in the Livers of Male Mice from Four Strains. Toxins (Basel) 2018; 10:487. [PMID: 30477109 PMCID: PMC6315709 DOI: 10.3390/toxins10120487] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 11/15/2018] [Accepted: 11/20/2018] [Indexed: 12/22/2022] Open
Abstract
Solasonine was reported to inhibit tumour cell growth in several different models. The in vivo toxicity of solasonine, the effects of genetic background on its toxicity, and its possible roles in regulating the expression of cyp450 family genes were still unclear and required characterisation. Here, Horn's assays were performed on male mice from four different strains, and the expression of cyp450 family genes in their livers was examined by RT-PCR and ELISA. Mice treated by intraperitoneal injection with high levels of solasonine showed immediate post-excitatory depression, intraperitoneal tissue adhesion, and dissolving of cells in the liver. Furthermore, these four mouse strains showed different toxicological sensitivity to solasonine. The strains, in decreasing order of LD50 value, rescuing speed of body weight, and more severe pathological symptoms, were KM, ICR, C57BL/6, and BALB/c. Interestingly, more cyp450 genes were downregulated at the mRNA and/or protein level in the livers of male mice from C57BL/6 or BALB/c strains than those from KM or ICR strains. These results suggest that (1) Solasonine has hepatic toxicity and downregulates cyp450 genes expression at transcriptional and/or post-transcriptional levels; (2) Genetic background is an important factor which can affect the in vivo toxicity; (3) Downregulation of cyp450 gene expression in the liver may be a clue to help understand whether or not a given strain is sensitive to solasonine; (4) Influences on the expression of cyp450 genes should be considered when using solasonine alone, or in combination with other drugs.
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Affiliation(s)
- Youbao Zhong
- Laboratory Animal Research Center for Science and Technology, Jiangxi University of Traditional Chinese Medicine, 1688 Meiling Road, Nanchang 330004, China.
- Key Laboratory of Pharmacology of Traditional Chinese Medicine in Jiangxi, Nanchang 330004, China.
| | - Shanshan Li
- Laboratory Animal Research Center for Science and Technology, Jiangxi University of Traditional Chinese Medicine, 1688 Meiling Road, Nanchang 330004, China.
- Key Laboratory of Pharmacology of Traditional Chinese Medicine in Jiangxi, Nanchang 330004, China.
| | - Liling Chen
- Laboratory Animal Research Center for Science and Technology, Jiangxi University of Traditional Chinese Medicine, 1688 Meiling Road, Nanchang 330004, China.
- Key Laboratory of Pharmacology of Traditional Chinese Medicine in Jiangxi, Nanchang 330004, China.
| | - Zhiyong Liu
- Laboratory Animal Research Center for Science and Technology, Jiangxi University of Traditional Chinese Medicine, 1688 Meiling Road, Nanchang 330004, China.
- Key Laboratory of Pharmacology of Traditional Chinese Medicine in Jiangxi, Nanchang 330004, China.
| | - Xiaoquan Luo
- Laboratory Animal Research Center for Science and Technology, Jiangxi University of Traditional Chinese Medicine, 1688 Meiling Road, Nanchang 330004, China.
- Key Laboratory of Pharmacology of Traditional Chinese Medicine in Jiangxi, Nanchang 330004, China.
| | - Peng Xu
- Laboratory Animal Research Center for Science and Technology, Jiangxi University of Traditional Chinese Medicine, 1688 Meiling Road, Nanchang 330004, China.
- Key Laboratory of Pharmacology of Traditional Chinese Medicine in Jiangxi, Nanchang 330004, China.
| | - Lai Chen
- Laboratory Animal Research Center for Science and Technology, Jiangxi University of Traditional Chinese Medicine, 1688 Meiling Road, Nanchang 330004, China.
- Key Laboratory of Pharmacology of Traditional Chinese Medicine in Jiangxi, Nanchang 330004, China.
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Chen B, Guo J, Wang S, Kang L, Deng Y, Li Y. Simulated Microgravity Altered the Metabolism of Loureirin B and the Expression of Major Cytochrome P450 in Liver of Rats. Front Pharmacol 2018; 9:1130. [PMID: 30369879 PMCID: PMC6194197 DOI: 10.3389/fphar.2018.01130] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Accepted: 09/18/2018] [Indexed: 12/31/2022] Open
Abstract
Loureirin B (LB) is the marker compound of dragon blood (DB), which exhibits great potentials in protecting astronauts' health against radiation and simulated microgravity (SM). Pharmacokinetics of LB is reported to be significantly altered by SM. Here, we investigated key metabolic features of LB in rat liver microsome (RLM) and the effects of SM on LB metabolism as well as on expression of major hepatic cytochrome P450 (CYP450) isoforms. Ten metabolites were tentatively identified based on fragmentation pathways using LC-MS/MS method and elimination kinetics of LB followed a typical Michaelis-Menten equation (V max was 1.32 μg/min/mg and K m was 13.33 μg/mL). CYP1A2, CYP2C11, CYP2D1, and CYP3A2 were involved in the metabolism of LB and the relative strength was: CYP3A2 > CYP2C11 > CYP2D1 > CYP1A2. Comparative studies suggested that elimination of LB in RLM was remarkably increased by 3-day and 14-day SM, and the generation of identified metabolites was affected as well. Additionally, 3-day and 14-day SM showed obvious regulatory effects on the expression of major CYP450 isoforms, which might contribute to the increased elimination of LB. The data provided supports for the application of DB as a protective agent and the reasonable use of current medications metabolized by hepatic CYP450 in space missions.
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Affiliation(s)
| | | | | | | | - Yulin Deng
- School of Life Science, Beijing Institute of Technology, Beijing, China
| | - Yujuan Li
- School of Life Science, Beijing Institute of Technology, Beijing, China
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Billington S, Ray AS, Salphati L, Xiao G, Chu X, Humphreys WG, Liao M, Lee CA, Mathias A, Hop CECA, Rowbottom C, Evers R, Lai Y, Kelly EJ, Prasad B, Unadkat JD. Transporter Expression in Noncancerous and Cancerous Liver Tissue from Donors with Hepatocellular Carcinoma and Chronic Hepatitis C Infection Quantified by LC-MS/MS Proteomics. Drug Metab Dispos 2018; 46:189-196. [PMID: 29138286 PMCID: PMC5776333 DOI: 10.1124/dmd.117.077289] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 10/19/2017] [Indexed: 12/11/2022] Open
Abstract
Protein expression of major hepatobiliary drug transporters (NTCP, OATPs, OCT1, BSEP, BCRP, MATE1, MRPs, and P-gp) in cancerous (C, n = 8) and adjacent noncancerous (NC, n = 33) liver tissues obtained from patients with chronic hepatitis C with hepatocellular carcinoma (HCV-HCC) were quantified by LC-MS/MS proteomics. Herein, we compare our results with our previous data from noninfected, noncirrhotic (control, n = 36) and HCV-cirrhotic (n = 30) livers. The amount of membrane protein yielded from NC and C HCV-HCC tissues decreased (31%, 67%) relative to control livers. In comparison with control livers, with the exception of NTCP, MRP2, and MATE1, transporter expression decreased in NC (38%-76%) and C (56%-96%) HCV-HCC tissues. In NC HCV-HCC tissues, NTCP expression increased (113%), MATE1 expression decreased (58%), and MRP2 expression was unchanged relative to control livers. In C HCV-HCC tissues, NTCP and MRP2 expression decreased (63%, 56%) and MATE1 expression was unchanged relative to control livers. Compared with HCV-cirrhotic livers, aside from NTCP, OCT1, BSEP, and MRP2, transporter expression decreased in NC (41%-71%) and C (54%-89%) HCV-HCC tissues. In NC HCV-HCC tissues, NTCP and MRP2 expression increased (362%, 142%), whereas OCT1 and BSEP expression was unchanged. In C HCV-HCC tissues, OCT1 and BSEP expression decreased (90%, 80%) relative to HCV-cirrhotic livers, whereas NTCP and MRP2 expression was unchanged. Expression of OATP2B1, BSEP, MRP2, and MRP3 decreased (56%-72%) in C HCV-HCC tissues in comparison with matched NC tissues (n = 8), but the expression of other transporters was unchanged. These data will be helpful in the future to predict transporter-mediated hepatocellular drug concentrations in patients with HCV-HCC.
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Affiliation(s)
- Sarah Billington
- Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
| | - Adrian S Ray
- Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
| | - Laurent Salphati
- Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
| | - Guangqing Xiao
- Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
| | - Xiaoyan Chu
- Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
| | - W Griffith Humphreys
- Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
| | - Mingxiang Liao
- Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
| | - Caroline A Lee
- Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
| | - Anita Mathias
- Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
| | - Cornelis E C A Hop
- Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
| | - Christopher Rowbottom
- Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
| | - Raymond Evers
- Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
| | - Yurong Lai
- Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
| | - Edward J Kelly
- Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
| | - Bhagwat Prasad
- Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
| | - Jashvant D Unadkat
- Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
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Atilano-Roque A, Roda G, Fogueri U, Kiser JJ, Joy MS. Effect of Disease Pathologies on Transporter Expression and Function. J Clin Pharmacol 2017; 56 Suppl 7:S205-21. [PMID: 27385176 DOI: 10.1002/jcph.768] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 05/08/2016] [Accepted: 05/10/2016] [Indexed: 12/12/2022]
Abstract
Transporters are important determinants of drug absorption, distribution, and excretion. The clinical relevance of drug transporters in drug disposition and toxicology depends on their localization in liver, kidney, and brain. There has been growing evidence regarding the importance of disease status on alterations in metabolizing enzymes and transporter proteins. This review focuses on uptake and efflux transporter proteins in liver, kidney, and brain and discusses mechanisms of altered transporter expression and function secondary to disease.
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Affiliation(s)
- Amandla Atilano-Roque
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA
| | - Gavriel Roda
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA
| | - Uma Fogueri
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA
| | - Jennifer J Kiser
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA
| | - Melanie S Joy
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA.,Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, Aurora, CO, USA
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Effect of Steady-State Faldaprevir on Pharmacokinetics of Atorvastatin or Rosuvastatin in Healthy Volunteers: A Prospective Open-Label, Fixed-Sequence Crossover Study. J Clin Pharmacol 2017; 57:1305-1314. [DOI: 10.1002/jcph.931] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2017] [Accepted: 04/03/2017] [Indexed: 12/12/2022]
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Thakkar N, Slizgi JR, Brouwer KLR. Effect of Liver Disease on Hepatic Transporter Expression and Function. J Pharm Sci 2017; 106:2282-2294. [PMID: 28465155 DOI: 10.1016/j.xphs.2017.04.053] [Citation(s) in RCA: 83] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 04/20/2017] [Accepted: 04/21/2017] [Indexed: 12/27/2022]
Abstract
Liver disease can alter the disposition of xenobiotics and endogenous substances. Regulatory agencies such as the Food and Drug Administration and the European Medicines Evaluation Agency recommend, if possible, studying the effect of liver disease on drugs under development to guide specific dose recommendations in these patients. Although extensive research has been conducted to characterize the effect of liver disease on drug-metabolizing enzymes, emerging data have implicated that the expression and function of hepatobiliary transport proteins also are altered in liver disease. This review summarizes recent developments in the field, which may have implications for understanding altered disposition, safety, and efficacy of new and existing drugs. A brief review of liver physiology and hepatic transporter localization/function is provided. Then, the expression and function of hepatic transporters in cholestasis, hepatitis C infection, hepatocellular carcinoma, human immunodeficiency virus infection, nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, and primary biliary cirrhosis are reviewed. In the absence of clinical data, nonclinical information in animal models is presented. This review aims to advance the understanding of altered expression and function of hepatic transporters in liver disease and the implications of such changes on drug disposition.
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Affiliation(s)
- Nilay Thakkar
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
| | - Jason R Slizgi
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
| | - Kim L R Brouwer
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599.
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Dietrich CG, Rau M, Jahn D, Geier A. Changes in drug transport and metabolism and their clinical implications in non-alcoholic fatty liver disease. Expert Opin Drug Metab Toxicol 2017; 13:625-640. [PMID: 28359183 DOI: 10.1080/17425255.2017.1314461] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION The incidence of non-alcoholic fatty liver disease (NAFLD) is rising, especially in Western countries. Drug treatment in patients with NAFLD is common since it is linked to other conditions like diabetes, obesity, and cardiovascular disease. Consequently, changes in drug metabolism may have serious clinical implications. Areas covered: A literature search for studies in animal models or patients with obesity, fatty liver, non-alcoholic steatohepatitis (NASH) or NASH cirrhosis published before November 2016 was performed. After discussing epidemiology and animal models for NAFLD, we summarized both basic as well as clinical studies investigating changes in drug transport and metabolism in NAFLD. Important drug groups were assessed separately with emphasis on clinical implications for drug treatment in patients with NAFLD. Expert opinion: Given the frequency of NAFLD even today, a high degree of drug treatment in NAFLD patients appears safe and well-tolerated despite considerable changes in hepatic uptake, distribution, metabolism and transport of drugs in these patients. NASH causes changes in biliary excretion, systemic concentrations, and renal handling of drugs leading to alterations in drug efficacy or toxicity under specific circumstances. Future clinical drug studies should focus on this special patient population in order to avoid serious adverse events in NAFLD patients.
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Affiliation(s)
- Christoph G Dietrich
- a Bethlehem Center of Health , Department of Medicine , Stolberg/Rhineland , Germany
| | - Monika Rau
- b Division of Hepatology, Department of Medicine II , University of Würzburg , Würzburg , Germany
| | - Daniel Jahn
- b Division of Hepatology, Department of Medicine II , University of Würzburg , Würzburg , Germany
| | - Andreas Geier
- b Division of Hepatology, Department of Medicine II , University of Würzburg , Würzburg , Germany
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Wijarnpreecha K, Thongprayoon C, Sanguankeo A, Upala S, Ungprasert P, Cheungpasitporn W. Hepatitis C infection and intrahepatic cholestasis of pregnancy: A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol 2017; 41:39-45. [PMID: 27542514 DOI: 10.1016/j.clinre.2016.07.004] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Revised: 06/25/2016] [Accepted: 07/07/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND/OBJECTIVES Hepatitis C virus (HCV) infection is a major cause of cirrhosis worldwide. Several studies have linked HCV infection to a higher risk of developing intrahepatic cholestasis of pregnancy (ICP), but some data demonstrates contradictory results. To further investigate the association and estimated risk of ICP in patients with HCV infection, we conducted this meta-analysis to summarize all available evidence. METHODS This study consists of two meta-analyses. A literature search was performed using MEDLINE and EMBASE from inception to January 2016. The first study included observational studies that reported relative risks, odds ratios, or hazard ratios of the associations between HCV infection and risk of ICP. The second analysis included studies comparing the risk of later HCV infection in ICP patients with those without ICP. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated using a random-effect, generic inverse variance method. RESULTS Three studies were included in the first analysis. The pooled OR of ICP in HCV-infected pregnant women compared to non-HCV pregnant women was 20.40 (95% CI, 9.39-44.33, I2=55%). Two studies were included in the second analysis. The pooled OR of later HCV infection among ICP patients compared to non-ICP patients was 4.08 (95% CI, 3.13-5.31, I2=0%). CONCLUSIONS Our meta-analysis demonstrates not only a higher risk of ICP among HCV-infected pregnant women but also an increased risk of later HCV infection among ICP patients. These findings suggest potential benefits of screening for hepatitis C in women with signs of ICP.
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Affiliation(s)
- Karn Wijarnpreecha
- Department of Internal Medicine, Bassett Medical Center, Cooperstown, NY, USA.
| | - Charat Thongprayoon
- Department of Internal Medicine, Bassett Medical Center, Cooperstown, NY, USA
| | - Anawin Sanguankeo
- Department of Internal Medicine, Bassett Medical Center, Cooperstown, NY, USA; Department of Preventive and Social Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Thailand
| | - Sikarin Upala
- Department of Internal Medicine, Bassett Medical Center, Cooperstown, NY, USA; Department of Preventive and Social Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Thailand
| | - Patompong Ungprasert
- Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA; Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
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Abstract
Despite the central role of the liver in drug metabolism, surprisingly there is lack of certainty in anticipating the extent of modification of the clearance of a given drug in a given patient. The intent of this review is to provide a conceptual framework in considering the impact of liver disease on drug disposition and reciprocally the impact of drug disposition on liver disease. It is proposed that improved understanding of the situation is gained by considering the issue as a special example of a drug-gene-environment interaction. This requires an integration of knowledge of the drug's properties, knowledge of the gene products involved in its metabolism, and knowledge of the pathophysiology of its disposition. This will enhance the level of predictability of drug disposition and toxicity for a drug of interest in an individual patient. It is our contention that advances in pharmacology, pharmacogenomics, and hepatology, together with concerted interests in the academic, regulatory, and pharmaceutical industry communities provide an ideal immediate environment to move from a qualitative reactive approach to quantitative proactive approach in individualizing patient therapy in liver disease.
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Affiliation(s)
- Nathalie K Zgheib
- a Department of Pharmacology and Toxicology , American University of Beirut Faculty of Medicine , Beirut , Lebanon
| | - Robert A Branch
- b Department of Medicine, School of Medicine , University of Pittsburgh , Pittsburgh , PA , USA
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Amacher DE. The regulation of human hepatic drug transporter expression by activation of xenobiotic-sensing nuclear receptors. Expert Opin Drug Metab Toxicol 2016; 12:1463-1477. [PMID: 27548410 DOI: 10.1080/17425255.2016.1223626] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
INTRODUCTION If a drug is found to be an inducer of hepatic drug metabolizing enzymes via activation of nuclear receptors such as pregnane X receptor (PXR) or constitutive androstane receptor (CAR), it is likely that drug transporters regulated through these same receptors will be induced as well. This review highlights what is currently known about the molecular mechanisms that regulate transporter expression and where the research is directed. Areas covered: This review is focused on publications that describe the role of activated hepatic nuclear receptors in the subsequent regulation of drug uptake and/or efflux transporters following exposure to xenobiotics. Expert opinion: Many of the published studies on the role of nuclear receptors in the regulation of drug transporters involve non-human test animals. But due to species response differences, these associations are not always applicable to humans. For this reason, some relevant human in vitro models have been developed, such as primary or cryopreserved human hepatocytes, human liver slices, or HepG2 or HuH7 cell lines transiently or stably transfected with PXR expression and reporter constructs as well as in vivo models such as PXR-humanized mice. These human-relevant test systems will continue to be developed and applied for the testing of investigational drugs.
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Hyrsova L, Smutny T, Trejtnar F, Pavek P. Expression of organic cation transporter 1 (OCT1): unique patterns of indirect regulation by nuclear receptors and hepatospecific gene regulation. Drug Metab Rev 2016; 48:139-58. [DOI: 10.1080/03602532.2016.1188936] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Lucie Hyrsova
- Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic
| | - Tomas Smutny
- Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic
| | - Frantisek Trejtnar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic
| | - Petr Pavek
- Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic
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Naito H, Jia X, Yetti H, Yanagiba Y, Tamada H, Kitamori K, Hayashi Y, Wang D, Kato M, Ishii A, Nakajima T. Importance of detoxifying enzymes in differentiating fibrotic development between SHRSP5/Dmcr and SHRSP rats. Environ Health Prev Med 2016; 21:368-381. [PMID: 27209494 DOI: 10.1007/s12199-016-0539-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2015] [Accepted: 05/09/2016] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES High-fat and -cholesterol diet (HFC) induced fibrotic steatohepatitis in stroke-prone spontaneously hypertensive rat (SHRSP) 5/Dmcr, the fifth substrain from SHRSP, by dysregulating bile acid (BA) kinetics. This study aimed to clarify the histopathological and BA kinetic differences in HFC-induced fibrosis between SHRSP5/Dmcr and SHRSP. METHODS Ten-week-old male SHRSP5/Dmcr and SHRSP were randomly allocated to groups and fed with either control diet or HFC for 2 and 8 weeks. The liver histopathology, biochemical features, and molecular signaling involved in BA kinetics were measured. RESULTS HFC caused more severe hepatocyte ballooning, macrovesicular steatosis and fibrosis in SHRSP5/Dmcr than in SHRSP. It was noted that fibrosis was disproportionately formed in retroperitoneal side of both strains. As for BA kinetics, HFC greatly increased the level of Cyp7a1 and Cyp7b1 to the same degree in both strains at 8 weeks, while multidrug resistance-associated protein 3 was greater in SHRSP5/Dmcr than SHRSP. The diet decreased the level of bile salt export pump by the same degree in both strains, while constitutive androstane receptor, pregnane X receptor, and UDP-glucuronosyltransferase activity more prominent in SHRSP5/Dmcr than SHRSP at 8 weeks. In the fibrosis-related genes, only expression of collagen, type I, alpha 1 mRNA was greater in SHRSP5/Dmcr than SHRSP. CONCLUSIONS The greater progression of fibrosis in SHRSP5/Dmcr induced by HFC may be due to greater suppression of UDP-glucuronosyltransferase activity detoxifying toxicants, such as hydrophobic BAs.
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Affiliation(s)
- Hisao Naito
- Department of Public Health, Fujita Health University School of Medicine, Dengakugakubo 1-98, Kutsukake-cho, Toyoake, 470-1192, Japan. .,Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan.
| | - Xiaofang Jia
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Husna Yetti
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yukie Yanagiba
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hazuki Tamada
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan.,College of Human Life and Environment, Kinjo Gakuin University, Nagoya, Japan
| | - Kazuya Kitamori
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan.,College of Human Life and Environment, Kinjo Gakuin University, Nagoya, Japan
| | - Yumi Hayashi
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Dong Wang
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masashi Kato
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Akira Ishii
- Department of Legal Medicine and Bioethics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tamie Nakajima
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan.,College of Life and Health Sciences, Chubu University, Kasugai, Japan
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Baba H, Tajiri K, Nagata K, Kawai K, Minemura M, Sugiyama T. Hyperbilirubinemia without Transaminitis during Combined Therapy with Daclatasvir and Asunaprevir. Case Rep Gastroenterol 2016; 10:352-359. [PMID: 27504082 PMCID: PMC4965544 DOI: 10.1159/000447486] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Accepted: 06/07/2016] [Indexed: 02/05/2023] Open
Abstract
Daclatasvir (DCV) and asunaprevir (ASV) are direct-acting antivirals (DAAs) used in the treatment of chronic hepatitis C virus (HCV) infection. Combined therapy with DCV and ASV shows high efficacy and safety even in patients with cirrhosis. We encountered a patient exhibiting severe hyperbilirubinemia during combined therapy, which is an unreported side effect of DCV and ASV. A 78-year-old woman with cirrhosis developed hyperbilirubinemia >10 mg/dl without transaminitis 3 weeks after starting combined therapy. We suspected DAAs-induced liver disorder and discontinued treatment, which resulted in the improvement of hyperbilirubinemia. Caution is required in the use of DAAs for patients with advanced cirrhosis.
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Affiliation(s)
- Hayato Baba
- The Third Department of Internal Medicine, Toyama University Hospital, Toyama, Japan
- Department of Education and Clinical Training, Toyama University Hospital, Toyama, Japan
| | - Kazuto Tajiri
- The Third Department of Internal Medicine, Toyama University Hospital, Toyama, Japan
| | - Kohei Nagata
- The Third Department of Internal Medicine, Toyama University Hospital, Toyama, Japan
| | - Kengo Kawai
- The Third Department of Internal Medicine, Toyama University Hospital, Toyama, Japan
| | - Masami Minemura
- The Third Department of Internal Medicine, Toyama University Hospital, Toyama, Japan
| | - Toshiro Sugiyama
- The Third Department of Internal Medicine, Toyama University Hospital, Toyama, Japan
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Dietrich CG, Götze O, Geier A. Molecular changes in hepatic metabolism and transport in cirrhosis and their functional importance. World J Gastroenterol 2016; 22:72-88. [PMID: 26755861 PMCID: PMC4698509 DOI: 10.3748/wjg.v22.i1.72] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 09/24/2015] [Accepted: 11/13/2015] [Indexed: 02/06/2023] Open
Abstract
Liver cirrhosis is the common endpoint of many hepatic diseases and represents a relevant risk for liver failure and hepatocellular carcinoma. The progress of liver fibrosis and cirrhosis is accompanied by deteriorating liver function. This review summarizes the regulatory and functional changes in phase I and phase II metabolic enzymes as well as transport proteins and provides an overview regarding lipid and glucose metabolism in cirrhotic patients. Interestingly, phase I enzymes are generally downregulated transcriptionally, while phase II enzymes are mostly preserved transcriptionally but are reduced in their function. Transport proteins are regulated in a specific way that resembles the molecular changes observed in obstructive cholestasis. Lipid and glucose metabolism are characterized by insulin resistance and catabolism, leading to the disturbance of energy expenditure and wasting. Possible non-invasive tests, especially breath tests, for components of liver metabolism are discussed. The heterogeneity and complexity of changes in hepatic metabolism complicate the assessment of liver function in individual patients. Additionally, studies in humans are rare, and species differences preclude the transferability of data from rodents to humans. In clinical practice, some established global scores or criteria form the basis for the functional evaluation of patients with liver cirrhosis, but difficult treatment decisions such as selection for transplantation or resection require further research regarding the application of existing non-invasive tests and the development of more specific tests.
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Yang T, Liu S, Zheng TH, Tao YY, Liu CH. Comparative pharmacokinetics and tissue distribution profiles of lignan components in normal and hepatic fibrosis rats after oral administration of Fuzheng Huayu recipe. JOURNAL OF ETHNOPHARMACOLOGY 2015; 166:305-312. [PMID: 25794805 DOI: 10.1016/j.jep.2015.03.024] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Revised: 01/05/2015] [Accepted: 03/09/2015] [Indexed: 06/04/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Fuzheng Huayu recipe (FZHY) is formulated on the basis of Chinese medicine theory in treating liver fibrosis. AIM OF THE STUDY To illuminate the influence of the pathological state of liver fibrosis on the pharmacokinetics and tissue distribution profiles of lignan components from FZHY. MATERIALS AND METHODS Male Wistar rats were randomly divided into normal group and Hepatic fibrosis group (induced by dimethylnitrosamine). Six lignan components were detected and quantified by ultrahigh performance liquid chromatography-tandem mass spectrometry(UHPLC-MS/MS)in the plasma and tissue of normal and hepatic fibrosis rats. RESULTS A rapid, sensitive and convenient UHPLC-MS/MS method has been developed for the simultaneous determination of six lignan components in different rat biological samples successfully. After oral administration of FZHY at a dose of 15g/kg, the pharmacokinetic behaviors of schizandrin A (SIA), schizandrin B (SIB), schizandrin C (SIC), schisandrol A (SOA), Schisandrol B (SOB) and schisantherin A (STA) have been significantly changed in hepatic fibrosis rats compared with the normal rats, and their AUC(0-t) values were increased by 235.09%, 388.44%, 223.30%, 669.30%, 295.08% and 267.63% orderly (P<0.05). Tissue distribution results showed the amount of SIA, SIB, SOA and SOB were significant increased in heart, lung, spleen and kidney of hepatic fibrosis rats compared with normal rats at most of the time point (P<0.05). Meanwhile, the result also reveals that the hepatic fibrosis could delay the peak time of lignans in liver. CONCLUSION The results proved that the established UHPLC-MS/MS method could be applied to the comparative study on pharmacokinetics and tissue distribution of lignan components in normal and hepatic fibrosis rats. The hepatic fibrosis could alter the pharmacokinetics and tissue distribution properties of lignan components in rats after administration of FZHY. The results might be helpful for guide the clinical application of this medicine.
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Affiliation(s)
- Tao Yang
- Institute of Liver Diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, China
| | - Shan Liu
- Institute of Liver Diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, China; School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Tian-Hui Zheng
- Institute of Liver Diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, China; School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Yan-Yan Tao
- Institute of Liver Diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, China; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, 528 Zhangheng Road, Shanghai 201203, China; E-Institute of TCM Internal Medicine, Shanghai Municipal Education Commission, 1200 Cailun Road, Shanghai 201203, China
| | - Cheng-Hai Liu
- Institute of Liver Diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, China; School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, 528 Zhangheng Road, Shanghai 201203, China; E-Institute of TCM Internal Medicine, Shanghai Municipal Education Commission, 1200 Cailun Road, Shanghai 201203, China.
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Moss DM, Marzolini C, Rajoli RKR, Siccardi M. Applications of physiologically based pharmacokinetic modeling for the optimization of anti-infective therapies. Expert Opin Drug Metab Toxicol 2015; 11:1203-17. [PMID: 25872900 DOI: 10.1517/17425255.2015.1037278] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION The pharmacokinetic properties of anti-infective drugs are a determinant part of treatment success. Pathogen replication is inhibited if adequate drug levels are achieved in target sites, whereas excessive drug concentrations linked to toxicity are to be avoided. Anti-infective distribution can be predicted by integrating in vitro drug properties and mathematical descriptions of human anatomy in physiologically based pharmacokinetic models. This method reduces the need for animal and human studies and is used increasingly in drug development and simulation of clinical scenario such as, for instance, drug-drug interactions, dose optimization, novel formulations and pharmacokinetics in special populations. AREAS COVERED We have assessed the relevance of physiologically based pharmacokinetic modeling in the anti-infective research field, giving an overview of mechanisms involved in model design and have suggested strategies for future applications of physiologically based pharmacokinetic models. EXPERT OPINION Physiologically based pharmacokinetic modeling provides a powerful tool in anti-infective optimization, and there is now no doubt that both industry and regulatory bodies have recognized the importance of this technology. It should be acknowledged, however, that major challenges remain to be addressed and that information detailing disease group physiology and anti-infective pharmacodynamics is required if a personalized medicine approach is to be achieved.
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Affiliation(s)
- Darren Michael Moss
- University of Liverpool, Institute of Translational Medicine, Molecular and Clinical Pharmacology , Liverpool , UK +44 0 151 794 8211 ; +44 0 151 794 5656 ;
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Avouac J, Palumbo-Zerr K, Ruzehaji N, Tomcik M, Zerr P, Dees C, Distler A, Beyer C, Schneider H, Distler O, Schett G, Allanore Y, Distler JHW. The nuclear receptor constitutive androstane receptor/NR1I3 enhances the profibrotic effects of transforming growth factor β and contributes to the development of experimental dermal fibrosis. Arthritis Rheumatol 2015; 66:3140-50. [PMID: 25155144 DOI: 10.1002/art.38819] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Accepted: 08/05/2014] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Nuclear receptors regulate cell growth, differentiation, and homeostasis. Selective nuclear receptors promote fibroblast activation, which leads to tissue fibrosis, the hallmark of systemic sclerosis (SSc). This study was undertaken to investigate the effects of constitutive androstane receptor (CAR)/NR1I3, an orphan nuclear receptor, on fibroblast activation and experimental dermal fibrosis. METHODS CAR expression was quantified by quantitative polymerase chain reaction, Western blotting, immunohistochemistry, and immunofluorescence. CAR expression was modulated by small molecules, small interfering RNA, forced overexpression, and site-directed mutagenesis. The effects of CAR activation were analyzed in cultured fibroblasts, in bleomycin-induced dermal fibrosis, and in mice overexpressing a constitutively active transforming growth factor β (TGFβ) receptor type I (TβRI-CA). RESULTS Up-regulation of CAR was detected in the skin and in dermal fibroblasts in SSc patients. Stimulation of healthy fibroblasts with TGFβ induced the expression of CAR messenger RNA and protein in a Smad-dependent manner. Pharmacologic activation or overexpression of CAR in healthy fibroblasts significantly increased the stimulatory effects of TGFβ on collagen synthesis and myofibroblast differentiation, and amplified the stimulatory effects of TGFβ on COL1A2 transcription activity. Treatment with CAR agonist increased the activation of canonical TGFβ signaling in murine models of SSc and exacerbated bleomycin-induced and TβRI-CA-induced fibrosis with increased dermal thickening, myofibroblast counts, and collagen accumulation. CONCLUSION Our findings indicate that CAR is up-regulated in SSc and regulates TGFβ signaling. Activation of CAR increases the profibrotic effects of TGFβ in cultured fibroblasts and in different preclinical models of SSc. Thus, inactivation of CAR might be a novel approach to target aberrant TGFβ signaling in SSc and in other fibrotic diseases.
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Affiliation(s)
- Jérôme Avouac
- University of Erlangen-Nuremberg, Erlangen, Germany; Paris Descartes University, INSERM U1016, and Cochin Hospital, AP-HP, Paris, France
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Ferslew BC, Köck K, Bridges AS, Brouwer KLR. Role of multidrug resistance-associated protein 4 in the basolateral efflux of hepatically derived enalaprilat. Drug Metab Dispos 2014; 42:1567-74. [PMID: 24958844 PMCID: PMC4152871 DOI: 10.1124/dmd.114.057554] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2014] [Accepted: 06/23/2014] [Indexed: 01/01/2023] Open
Abstract
Hepatic uptake and efflux transporters govern the systemic and hepatic exposure of many drugs and metabolites. Enalapril is a pharmacologically inactive prodrug of enalaprilat. Following oral administration, enalapril is converted to enalaprilat in hepatocytes and undergoes translocation into the systemic circulation to exert its pharmacologic effect by inhibiting angiotensin-converting enzyme. Although the transport proteins governing hepatic uptake of enalapril and the biliary excretion of enalapril and enalaprilat are well established, it remains unknown how hepatically derived enalaprilat translocates across the basolateral membrane into the systemic circulation. In this study, the role of ATP-binding cassette transporters in the hepatic basolateral efflux of enalaprilat was investigated using membrane vesicles. ATP-dependent uptake of enalaprilat into vesicles expressing multidrug resistance-associated protein (MRP) 4 was significantly greater (∼3.8-fold) than in control vesicles. In contrast, enalaprilat was not transported to a significant extent by MRP3, and enalapril was not transported by either MRP3 or MRP4. The functional importance of MRP4 in the basolateral excretion of derived enalaprilat was evaluated using a novel basolateral efflux protocol developed in human sandwich-cultured hepatocytes. Under normal culture conditions, the mean intrinsic basolateral efflux clearance (CLint ,basolateral) of enalaprilat was 0.026 ± 0.012 µl/min; enalaprilat CLint,basolateral was significantly reduced to 0.009 ± 0.009 µl/min by pretreatment with the pan-MRP inhibitor MK-571. Results suggest that hepatically derived enalaprilat is excreted across the hepatic basolateral membrane by MRP4. Changes in MRP4-mediated basolateral efflux may alter the systemic concentrations of this active metabolite, and potentially the efficacy of enalapril.
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Affiliation(s)
- Brian C Ferslew
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy (B.C.F., K.K., K.L.R.B.) and Department of Pathology, UNC School of Medicine (A.S.B.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Kathleen Köck
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy (B.C.F., K.K., K.L.R.B.) and Department of Pathology, UNC School of Medicine (A.S.B.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Arlene S Bridges
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy (B.C.F., K.K., K.L.R.B.) and Department of Pathology, UNC School of Medicine (A.S.B.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Kim L R Brouwer
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy (B.C.F., K.K., K.L.R.B.) and Department of Pathology, UNC School of Medicine (A.S.B.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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Anwer MS, Stieger B. Sodium-dependent bile salt transporters of the SLC10A transporter family: more than solute transporters. PFLUGERS ARCHIV : EUROPEAN JOURNAL OF PHYSIOLOGY 2013. [PMID: 24196564 DOI: 10.1007/s00424‐013‐1367‐0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The SLC10A transporter gene family consists of seven members and substrates transported by three members (SLC10A1, SLC10A2 and SLC10A6) are Na(+)-dependent. SLC10A1 (sodium taurocholate cotransporting polypeptide [NTCP]) and SLC10A2 (apical sodium-dependent bile salt transporter [ASBT]) transport bile salts and play an important role in maintaining enterohepatic circulation of bile salts. Solutes other than bile salts are also transported by NTCP. However, ASBT has not been shown to be a transporter for non-bile salt substrates. While the transport function of NTCP can potentially be used as liver function test, interpretation of such a test may be complicated by altered expression of NTCP in diseases and presence of drugs that may inhibit NTCP function. Transport of bile salts by NTCP and ASBT is inhibited by a number of drugs and it appears that ASBT is more permissive to drug inhibition than NTCP. The clinical significance of this inhibition in drug disposition and drug-drug interaction remains to be determined. Both NCTP and ASBT undergo post-translational regulations that involve phosphorylation/dephosphorylation, translocation to and retrieval from the plasma membrane and degradation by the ubiquitin-proteasome system. These posttranslational regulations are mediated via signaling pathways involving cAMP, calcium, nitric oxide, phosphoinositide-3-kinase (PI3K), protein kinase C (PKC) and protein phosphatases. There appears to be species difference in the substrate specificity and the regulation of plasma membrane localization of human and rodent NTCP. These differences should be taken into account when extrapolating rodent data for human clinical relevance and developing novel therapies. NTCP has recently been shown to play an important role in HBV and HDV infection by serving as a receptor for entry of these viruses into hepatocytes.
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Affiliation(s)
- M Sawkat Anwer
- Department of Biomedical Sciences, Cummings School of Veterinary Medicine, Tufts University, 200 Westboro Road, North Grafton, MA, 01536, USA,
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Pierre S, Chevallier A, Teixeira-Clerc F, Ambolet-Camoit A, Bui LC, Bats AS, Fournet JC, Fernandez-Salguero P, Aggerbeck M, Lotersztajn S, Barouki R, Coumoul X. Aryl hydrocarbon receptor-dependent induction of liver fibrosis by dioxin. Toxicol Sci 2013; 137:114-24. [PMID: 24154488 DOI: 10.1093/toxsci/kft236] [Citation(s) in RCA: 94] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The contribution of environmental pollutants to liver fibrosis is an important and poorly explored issue. In vitro studies suggest that the environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other aryl hydrocarbon receptor (AhR) ligands induce several genes that are known to be upregulated during liver fibrosis. Our aim was to determine whether exposure to such pollutants can lead to liver fibrosis and to characterize the mechanisms of action. Mice were treated for 2, 14, or 42 days, once a week with 25 µg/kg of TCDD. Gene and protein expression, in vitro and in vivo, as well as liver histology were investigated for each treatment. Treatment of mice with TCDD for 2 weeks modified the hepatic expression of markers of fibrosis such as collagen 1A1 and α-smooth muscle actin. This is not observed in AhR knockout mice. Following 6 weeks of treatment, histological features of murine hepatic fibrosis became apparent. In parallel, the levels of inflammatory cytokines (interleukin-1 beta, tumor necrosis factor α) and of markers of activated fibroblasts(fibroblast-specific protein 1) were found to be upregulated. Interestingly, we also found increased expression of genes of the TGF-β pathway and a concomitant decrease of miR-200a levels. Because the transcription factors of the Snail family were shown to be involved in liver fibrosis, we studied their regulation by TCDD. Two members of the Snail family were increased, whereas their negative targets, the epithelial marker E-cadherin and Claudin 1, were decreased. Further, the expression of mesenchymal markers was increased. Finally, we confirmed that Snai2 is a direct transcriptional target of TCDD in the human hepatocarcinoma cell line, HepG2. The AhR ligand, TCDD, induces hepatic fibrosis by directly regulating profibrotic pathways.
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Affiliation(s)
- Stéphane Pierre
- * INSERM UMR-S 747, Toxicologie Pharmacologie et Signalisation Cellulaire, Paris, France
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Pfeifer ND, Hardwick RN, Brouwer KLR. Role of hepatic efflux transporters in regulating systemic and hepatocyte exposure to xenobiotics. Annu Rev Pharmacol Toxicol 2013; 54:509-35. [PMID: 24160696 DOI: 10.1146/annurev-pharmtox-011613-140021] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Hepatic efflux transporters include numerous well-known and emerging proteins localized to the canalicular or basolateral membrane of the hepatocyte that are responsible for the excretion of drugs into the bile or blood, respectively. Altered function of hepatic efflux transporters due to drug-drug interactions, genetic variation, and/or disease states may lead to changes in xenobiotic exposure in the hepatocyte and/or systemic circulation. This review focuses on transport proteins involved in the hepatocellular efflux of drugs and metabolites, discusses mechanisms of altered transporter function as well as the interplay between multiple transport pathways, and highlights the importance of considering intracellular unbound concentrations of transporter substrates and/or inhibitors. Methods to evaluate hepatic efflux transport and predict the effects of impaired transporter function on systemic and hepatocyte exposure are discussed, and the sandwich-cultured hepatocyte model to evaluate comprehensively the role of hepatic efflux in the hepatobiliary disposition of xenobiotics is characterized.
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Affiliation(s)
- Nathan D Pfeifer
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; ,
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Sodium-dependent bile salt transporters of the SLC10A transporter family: more than solute transporters. Pflugers Arch 2013; 466:77-89. [PMID: 24196564 DOI: 10.1007/s00424-013-1367-0] [Citation(s) in RCA: 100] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2013] [Revised: 09/16/2013] [Accepted: 09/20/2013] [Indexed: 12/19/2022]
Abstract
The SLC10A transporter gene family consists of seven members and substrates transported by three members (SLC10A1, SLC10A2 and SLC10A6) are Na(+)-dependent. SLC10A1 (sodium taurocholate cotransporting polypeptide [NTCP]) and SLC10A2 (apical sodium-dependent bile salt transporter [ASBT]) transport bile salts and play an important role in maintaining enterohepatic circulation of bile salts. Solutes other than bile salts are also transported by NTCP. However, ASBT has not been shown to be a transporter for non-bile salt substrates. While the transport function of NTCP can potentially be used as liver function test, interpretation of such a test may be complicated by altered expression of NTCP in diseases and presence of drugs that may inhibit NTCP function. Transport of bile salts by NTCP and ASBT is inhibited by a number of drugs and it appears that ASBT is more permissive to drug inhibition than NTCP. The clinical significance of this inhibition in drug disposition and drug-drug interaction remains to be determined. Both NCTP and ASBT undergo post-translational regulations that involve phosphorylation/dephosphorylation, translocation to and retrieval from the plasma membrane and degradation by the ubiquitin-proteasome system. These posttranslational regulations are mediated via signaling pathways involving cAMP, calcium, nitric oxide, phosphoinositide-3-kinase (PI3K), protein kinase C (PKC) and protein phosphatases. There appears to be species difference in the substrate specificity and the regulation of plasma membrane localization of human and rodent NTCP. These differences should be taken into account when extrapolating rodent data for human clinical relevance and developing novel therapies. NTCP has recently been shown to play an important role in HBV and HDV infection by serving as a receptor for entry of these viruses into hepatocytes.
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Abstract
Cholestatic liver diseases encompass a wide spectrum of disorders with different causes, resulting in impaired bile flow and accumulation of bile acids and other potentially hepatotoxic cholephils. The understanding of the molecular mechanisms of bile formation and cholestasis has recently improved significantly through new insights into nuclear receptor (patho)biology. Nuclear receptors are ligand-activated transcription factors, which act as central players in the regulation of genes responsible for elimination and detoxification of biliary constituents accumulating in cholestasis. They also control other pathophysiologic processes such as inflammation, fibrogenesis, and carcinogenesis involved in the pathogenesis and disease progression of cholestasis liver diseases.
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Affiliation(s)
- Emina Halilbasic
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Anna Baghdasaryan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Corresponding author. Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Vienna, Austria.
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Theile D, Haefeli WE, Seitz HK, Millonig G, Weiss J, Mueller S. Association of liver stiffness with hepatic expression of pharmacokinetically important genes in alcoholic liver disease. Alcohol Clin Exp Res 2012; 37 Suppl 1:E17-22. [PMID: 22827451 DOI: 10.1111/j.1530-0277.2012.01901.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2012] [Accepted: 05/17/2012] [Indexed: 12/23/2022]
Abstract
BACKGROUND Enhanced drug elimination in alcoholics remains largely indefinable. In contrast, the reduced elimination of drugs in patients with advanced alcoholic liver disease (ALD) is normally owing to hepatic end-stage disease such as cirrhosis. We here study the mRNA expression of various hepatic drug metabolizing enzymes and transporters in association with liver stiffness (LS) being a novel noninvasive parameter for the assessment of cirrhosis to unravel the dynamic relationship between ALD and determinants of pharmacokinetics such as drug metabolizing enzymes and transporters. METHODS We quantified mRNA expression levels of various cytochrome P-450 isoenzymes (CYPs) and drug transporters in 26 liver specimens of chronic alcoholics and 5 controls by quantitative polymerase chain reaction. In addition, liver histology, clinical data, and LS evaluated by transient elastography (Fibroscan) were obtained. RESULTS Eighteen patients had a normal or moderate LS < 8 kPa (69.2%), while in the remaining 8 patients (30.7%) advanced F3 or F4 fibrosis could be established with an LS > 8 kPa. Overall, CYP3A4, CYP2E1, and solute carrier organic anion transporter 1B1 (SLCO1B1) were negatively correlated with increasing LS. CYPs and drug transporters tended to be up-regulated in alcoholics without advanced fibrosis (LS < 8.0 kPa) compared to healthy controls supporting data of boosted drug elimination in alcoholics without advanced ALD. However, in alcoholics with severely increased LS (>8 kPa), expression levels of CYP2E1, SLC22A2, and SLCO1B1 were significantly lower. CONCLUSIONS In conclusion, CYPs and drug transporters seem to be induced in chronic alcoholics without irreversible liver damage but decline in case of manifest cirrhosis. Our study also suggests that noninvasive measurements of LS could be useful for pharmacokinetic predictions and individualized pharmacotherapy.
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Affiliation(s)
- Dirk Theile
- Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany
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