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Wu N, Bayatpour S, Hylemon PB, Aseem SO, Brindley PJ, Zhou H. Gut Microbiome and Bile Acid Interactions: Mechanistic Implications for Cholangiocarcinoma Development, Immune Resistance, and Therapy. THE AMERICAN JOURNAL OF PATHOLOGY 2025; 195:397-408. [PMID: 39730075 PMCID: PMC11841492 DOI: 10.1016/j.ajpath.2024.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 11/05/2024] [Accepted: 11/12/2024] [Indexed: 12/29/2024]
Abstract
Cholangiocarcinoma (CCA) is a rare but highly malignant carcinoma of bile duct epithelial cells with a poor prognosis. The major risk factors of CCA carcinogenesis and progression are cholestatic liver diseases. The key feature of primary sclerosing cholangitis and primary biliary cholangitis is chronic cholestasis. It indicates a slowdown of hepatocyte secretion of biliary lipids and metabolites into bile as well as a slowdown of enterohepatic circulation (bile acid recirculation) of bile acids with dysbiosis of the gut microbiome. This leads to enterohepatic recirculation and an increase of toxic secondary bile acids. Alterations of serum and liver bile acid compositions via the disturbed enterohepatic circulation of bile acids and the disturbance of the gut microbiome then activate a series of hepatic and cancer cell signaling pathways that promote CCA carcinogenesis and progression. This review focuses on the mechanistic roles of bile acids and the gut microbiome in the pathogenesis and progression of CCA. It also evaluates the therapeutic potential of targeting the gut microbiome and bile acid-mediated signaling pathways for the therapy and prophylaxis of CCA.
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Affiliation(s)
- Nan Wu
- Department of Microbiology and Immunology, Virginia Commonwealth University and Richmond Veterans Affairs Medical Center, Richmond, Virginia
| | - Sareh Bayatpour
- Department of Microbiology and Immunology, Virginia Commonwealth University and Richmond Veterans Affairs Medical Center, Richmond, Virginia
| | - Phillip B Hylemon
- Department of Microbiology and Immunology, Virginia Commonwealth University and Richmond Veterans Affairs Medical Center, Richmond, Virginia; Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
| | - Sayed O Aseem
- Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, School of Medicine, Virginia Commonwealth University, Richmond, Virginia; Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia
| | - Paul J Brindley
- Department of Microbiology, Immunology and Tropical Medicine, and Research Center for Neglected Diseases of Poverty, School of Medicine and Health Sciences, George Washington University, Washington, District of Columbia
| | - Huiping Zhou
- Department of Microbiology and Immunology, Virginia Commonwealth University and Richmond Veterans Affairs Medical Center, Richmond, Virginia; Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, School of Medicine, Virginia Commonwealth University, Richmond, Virginia.
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Marin JJG, Cives-Losada C, Macias RIR, Romero MR, Marijuan RP, Hortelano-Hernandez N, Delgado-Calvo K, Villar C, Gonzalez-Santiago JM, Monte MJ, Asensio M. Impact of liver diseases and pharmacological interactions on the transportome involved in hepatic drug disposition. Biochem Pharmacol 2024; 228:116166. [PMID: 38527556 DOI: 10.1016/j.bcp.2024.116166] [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: 01/18/2024] [Revised: 03/14/2024] [Accepted: 03/22/2024] [Indexed: 03/27/2024]
Abstract
The liver plays a pivotal role in drug disposition owing to the expression of transporters accounting for the uptake at the sinusoidal membrane and the efflux across the basolateral and canalicular membranes of hepatocytes of many different compounds. Moreover, intracellular mechanisms of phases I and II biotransformation generate, in general, inactive compounds that are more polar and easier to eliminate into bile or refluxed back toward the blood for their elimination by the kidneys, which becomes crucial when the biliary route is hampered. The set of transporters expressed at a given time, i.e., the so-called transportome, is encoded by genes belonging to two gene superfamilies named Solute Carriers (SLC) and ATP-Binding Cassette (ABC), which account mainly, but not exclusively, for the uptake and efflux of endogenous substances and xenobiotics, which include many different drugs. Besides the existence of genetic variants, which determines a marked interindividual heterogeneity regarding liver drug disposition among patients, prevalent diseases, such as cirrhosis, non-alcoholic steatohepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, viral hepatitis, hepatocellular carcinoma, cholangiocarcinoma, and several cholestatic liver diseases, can alter the transportome and hence affect the pharmacokinetics of drugs used to treat these patients. Moreover, hepatic drug transporters are involved in many drug-drug interactions (DDI) that challenge the safety of using a combination of agents handled by these proteins. Updated information on these questions has been organized in this article by superfamilies and families of members of the transportome involved in hepatic drug disposition.
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Affiliation(s)
- Jose J G Marin
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain.
| | - Candela Cives-Losada
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Rocio I R Macias
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Marta R Romero
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Rebeca P Marijuan
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain
| | | | - Kevin Delgado-Calvo
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain
| | - Carmen Villar
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain; Department of Gastroenterology and Hepatology, University Hospital of Salamanca, Salamanca, Spain
| | - Jesus M Gonzalez-Santiago
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain; Department of Gastroenterology and Hepatology, University Hospital of Salamanca, Salamanca, Spain
| | - Maria J Monte
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Maitane Asensio
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
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Helmke S, Kittelson J, Imperial JC, McRae MP, Everson GT. The Oral Cholate Challenge Test Quantifies Risk for Liver-Related Clinical Outcomes in Primary Sclerosing Cholangitis. GASTRO HEP ADVANCES 2024; 3:944-953. [PMID: 39286620 PMCID: PMC11403427 DOI: 10.1016/j.gastha.2024.07.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 07/09/2024] [Indexed: 09/19/2024]
Abstract
Background and Aims We quantified hepatic functional impairment using quantitative function tests and linked severity of functional impairment to liver-related complications and outcome in primary sclerosing cholangitis. Methods Forty-seven patients had baseline testing, and 40 were retested after 1 year. For each test, cholates labeled with cold, nonradioactive isotopes were administered orally (DuO, SHUNT tests) and intravenously (SHUNT test), and blood was analyzed at 20 and 60 minutes (DuO), or 0, 5, 20, 45, 60, and 90 minutes (SHUNT). Disease severity index (DSI), hepatic reserve (HR%), and portal-systemic shunting (SHUNT%) were calculated. Results Three subgroups with low, moderate, and high disease severity were defined from the age-adjusted results for DSI, HR%, and SHUNT%. Standard laboratory tests, clinical scores, cytokine levels, and clinical outcome correlated with these subgroups. In univariate analysis of baseline tests, SHUNT% was a strong predictor of clinical outcome (n = 13 of 47; areas under the receiver operating characteristic curve, 0.84DuO, 0.90SHUNT). A model combining SHUNT%, DSI (or HR%), platelet count, and changes from baseline was most predictive of outcome (n = 10 of 40; areas under the receiver operating characteristic curve, 0.95DuO, 0.96SHUNT). Conclusion DSI, HR%, and SHUNT% identified subgroups of primary sclerosing cholangitis based on the age-related severity of hepatic impairment that predicted risk for liver-related clinical outcome. Further study is warranted to confirm and validate these intriguing findings both in studies of natural progression of primary sclerosing cholangitis and in clinical trials. DuO enhances the utility of quantitative liver function testing.
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Affiliation(s)
- Steve Helmke
- Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- HepQuant LLC, Denver, Colorado
| | - John Kittelson
- Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | | | | | - Gregory T Everson
- Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- HepQuant LLC, Denver, Colorado
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Trivedi PJ, Hirschfield GM, Adams DH, Vierling JM. Immunopathogenesis of Primary Biliary Cholangitis, Primary Sclerosing Cholangitis and Autoimmune Hepatitis: Themes and Concepts. Gastroenterology 2024; 166:995-1019. [PMID: 38342195 DOI: 10.1053/j.gastro.2024.01.049] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 01/21/2024] [Accepted: 01/28/2024] [Indexed: 02/13/2024]
Abstract
Autoimmune liver diseases include primary biliary cholangitis, primary sclerosing cholangitis, and autoimmune hepatitis, a family of chronic immune-mediated disorders that target hepatocytes and cholangiocytes. Treatments remain nonspecific, variably effective, and noncurative, and the need for liver transplantation is disproportionate to their rarity. Development of effective therapies requires better knowledge of pathogenic mechanisms, including the roles of genetic risk, and how the environment and gut dysbiosis cause immune cell dysfunction and aberrant bile acid signaling. This review summarizes key etiologic and pathogenic concepts and themes relevant for clinical practice and how such learning can guide the development of new therapies for people living with autoimmune liver diseases.
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Affiliation(s)
- Palak J Trivedi
- National Institute for Health Research Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom; Liver Unit, University Hospitals Birmingham, Birmingham, United Kingdom; Institute of Translational Medicine, University of Birmingham, Birmingham, United Kingdom.
| | - Gideon M Hirschfield
- Division of Gastroenterology and Hepatology, Toronto Centre for Liver Disease, University of Toronto, Toronto, Ontario, Canada
| | - David H Adams
- National Institute for Health Research Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom; Liver Unit, University Hospitals Birmingham, Birmingham, United Kingdom
| | - John M Vierling
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas; Division of Abdominal Transplantation, Department of Surgery, Baylor College of Medicine, Houston, Texas.
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Zhang Y, Chen SJ, Chen C, Chen XQ, Chatterjee S, Shuster DJ, Dexter H, Armstrong L, Joshi EM, Yang Z, Shen H. Repression of Organic Anion Transporting Polypeptide (OATP) 1B Expression and Increase of Plasma Coproporphyrin Level as Evidence for OATP1B Downregulation in Cynomolgus Monkeys Treated with Chenodeoxycholic Acid. Drug Metab Dispos 2022; 50:1077-1086. [PMID: 35636769 DOI: 10.1124/dmd.122.000875] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 05/12/2022] [Indexed: 11/22/2022] Open
Abstract
Farnesoid X receptor (FXR) is a nuclear receptor known to markedly alter expression of major transporters and enzymes in the liver. However, its effects toward organic anion transporting polypeptides (OATP) 1B1 and 1B3 remain poorly characterized. Therefore, the present study was aimed at determining the effects of chenodeoxycholic acid (CDCA), a naturally occurring FXR agonist, on OATP1B expression in cynomolgus monkeys. Multiple administrations of 50 and 100 mg/kg of CDCA were first shown to significantly repress mRNA expression of SLCO1B1/3 approximately 60% to 80% in monkey livers. It also suppressed cytochrome P450 (CYP)7A1-mRNA and induced OSTα/β-mRNA, which are well known targets of FXR and determinants of bile acid homeostasis. CDCA concomitantly decreased OATP1B protein abundance by approximately 60% in monkey liver. In contrast, multiple doses of 15 mg/kg rifampin (RIF), a pregnane X receptor agonist, had no effect on hepatic OATP1B protein, although it induced the intestinal P-glycoprotein and MR2 proteins by ∼2-fold. Moreover, multiple doses of CDCA resulted in a steady ∼2- to 10-fold increase of the OATP1B biomarkers coproporphyrins (CPs) in the plasma samples collected prior to each CDCA dose. Additionally, 3.4- to 11.2-fold increases of CPI and CPIII areas under the curve were observed after multiple administrations compared with the single dose and vehicle administration dosing groups. Taken together, these data suggest that CDCA represses the expression of OATP1B1 and OATP1B3 in monkeys. Further investigation of OATP1B downregulation by FXR in humans is warranted, as such downregulation effects may be involved in bile acid homeostasis and potential drug interactions in man. SIGNIFICANCE STATEMENT: Using gene expression and proteomics tools, as well as endogenous biomarker data, for the first time, we have demonstrated that OATP1B expression was suppressed and its activity was reduced in the cynomolgus monkeys following oral administration of 50 and 100 mg/kg/day of chenodeoxycholic acid (CDCA), a Farnesoid X receptor agonist, for 8 days. These results lead to a better understanding of OATP1B downregulation by CDCA and its role on bile acid and drug disposition.
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Affiliation(s)
- Yueping Zhang
- Drug Metabolism and Pharmacokinetics (Y.Z., C.C, E.M.J., Z.Y., H.S.), Discovery Toxicology (S.-J.C., L.A.), Discovery Pharmaceutics (X.-Q.C.), and Veterinary Sciences (D.J.S., H.D.), Bristol Myers Squibb Company, Princeton, New Jersey; and Drug Metabolism and Pharmacokinetics (S.-J.C.), Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Bangalore, India
| | - Shen-Jue Chen
- Drug Metabolism and Pharmacokinetics (Y.Z., C.C, E.M.J., Z.Y., H.S.), Discovery Toxicology (S.-J.C., L.A.), Discovery Pharmaceutics (X.-Q.C.), and Veterinary Sciences (D.J.S., H.D.), Bristol Myers Squibb Company, Princeton, New Jersey; and Drug Metabolism and Pharmacokinetics (S.-J.C.), Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Bangalore, India
| | - Cliff Chen
- Drug Metabolism and Pharmacokinetics (Y.Z., C.C, E.M.J., Z.Y., H.S.), Discovery Toxicology (S.-J.C., L.A.), Discovery Pharmaceutics (X.-Q.C.), and Veterinary Sciences (D.J.S., H.D.), Bristol Myers Squibb Company, Princeton, New Jersey; and Drug Metabolism and Pharmacokinetics (S.-J.C.), Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Bangalore, India
| | - Xue-Qing Chen
- Drug Metabolism and Pharmacokinetics (Y.Z., C.C, E.M.J., Z.Y., H.S.), Discovery Toxicology (S.-J.C., L.A.), Discovery Pharmaceutics (X.-Q.C.), and Veterinary Sciences (D.J.S., H.D.), Bristol Myers Squibb Company, Princeton, New Jersey; and Drug Metabolism and Pharmacokinetics (S.-J.C.), Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Bangalore, India
| | - Sagnik Chatterjee
- Drug Metabolism and Pharmacokinetics (Y.Z., C.C, E.M.J., Z.Y., H.S.), Discovery Toxicology (S.-J.C., L.A.), Discovery Pharmaceutics (X.-Q.C.), and Veterinary Sciences (D.J.S., H.D.), Bristol Myers Squibb Company, Princeton, New Jersey; and Drug Metabolism and Pharmacokinetics (S.-J.C.), Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Bangalore, India
| | - David J Shuster
- Drug Metabolism and Pharmacokinetics (Y.Z., C.C, E.M.J., Z.Y., H.S.), Discovery Toxicology (S.-J.C., L.A.), Discovery Pharmaceutics (X.-Q.C.), and Veterinary Sciences (D.J.S., H.D.), Bristol Myers Squibb Company, Princeton, New Jersey; and Drug Metabolism and Pharmacokinetics (S.-J.C.), Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Bangalore, India
| | - Heather Dexter
- Drug Metabolism and Pharmacokinetics (Y.Z., C.C, E.M.J., Z.Y., H.S.), Discovery Toxicology (S.-J.C., L.A.), Discovery Pharmaceutics (X.-Q.C.), and Veterinary Sciences (D.J.S., H.D.), Bristol Myers Squibb Company, Princeton, New Jersey; and Drug Metabolism and Pharmacokinetics (S.-J.C.), Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Bangalore, India
| | - Laura Armstrong
- Drug Metabolism and Pharmacokinetics (Y.Z., C.C, E.M.J., Z.Y., H.S.), Discovery Toxicology (S.-J.C., L.A.), Discovery Pharmaceutics (X.-Q.C.), and Veterinary Sciences (D.J.S., H.D.), Bristol Myers Squibb Company, Princeton, New Jersey; and Drug Metabolism and Pharmacokinetics (S.-J.C.), Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Bangalore, India
| | - Elizabeth M Joshi
- Drug Metabolism and Pharmacokinetics (Y.Z., C.C, E.M.J., Z.Y., H.S.), Discovery Toxicology (S.-J.C., L.A.), Discovery Pharmaceutics (X.-Q.C.), and Veterinary Sciences (D.J.S., H.D.), Bristol Myers Squibb Company, Princeton, New Jersey; and Drug Metabolism and Pharmacokinetics (S.-J.C.), Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Bangalore, India
| | - Zheng Yang
- Drug Metabolism and Pharmacokinetics (Y.Z., C.C, E.M.J., Z.Y., H.S.), Discovery Toxicology (S.-J.C., L.A.), Discovery Pharmaceutics (X.-Q.C.), and Veterinary Sciences (D.J.S., H.D.), Bristol Myers Squibb Company, Princeton, New Jersey; and Drug Metabolism and Pharmacokinetics (S.-J.C.), Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Bangalore, India
| | - Hong Shen
- Drug Metabolism and Pharmacokinetics (Y.Z., C.C, E.M.J., Z.Y., H.S.), Discovery Toxicology (S.-J.C., L.A.), Discovery Pharmaceutics (X.-Q.C.), and Veterinary Sciences (D.J.S., H.D.), Bristol Myers Squibb Company, Princeton, New Jersey; and Drug Metabolism and Pharmacokinetics (S.-J.C.), Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Bangalore, India
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Downregulated expression of organic anion transporting polypeptide (Oatp) 2b1 in the small intestine of rats with acute kidney injury. Drug Metab Pharmacokinet 2021; 40:100411. [PMID: 34284282 DOI: 10.1016/j.dmpk.2021.100411] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 05/31/2021] [Accepted: 06/10/2021] [Indexed: 12/14/2022]
Abstract
The expression of transporters on the apical and basal membranes of renal tubular cells is modulated under acute kidney injury (AKI). However, little is known about alterations in non-renal transporters in the tissues other than the kidney under AKI situation. This study aimed to assess the modulation of organic anion transporting polypeptide (Oatp) 1a2 and Oatp2b1 expression/function in the small intestine of rats with drug-induced AKI. AKI was induced by intraperitoneal administration of cisplatin at a dose of 5 mg/kg. On day 3 after cisplatin administration, morphological changes in the small intestine, Oatp1a2 and Oatp2b1 expression, and absorption of pravastatin and theophylline were evaluated. Non-negligible atrophy was observed in the jejunum and ileum of the AKI rats. However, the absorption of theophylline was not affected. While intestinal Oatp2b1 expression was markedly decreased in the AKI rats, no alteration was observed in Oatp1a2 expression. The plasma levels of pravastatin after intraluminal administration declined significantly in the AKI rats. However, no such decline was observed after intravenous administration. This study suggested that the responses of intestinal Oatps to experimentally induced AKI was not unidirectional and that pravastatin absorption was governed more potently by Oatp2b1 than by Oatp1a2 in the rat intestine.
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Gerner B, Scherf-Clavel O. Physiologically Based Pharmacokinetic Modelling of Cabozantinib to Simulate Enterohepatic Recirculation, Drug-Drug Interaction with Rifampin and Liver Impairment. Pharmaceutics 2021; 13:pharmaceutics13060778. [PMID: 34067429 PMCID: PMC8224782 DOI: 10.3390/pharmaceutics13060778] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/19/2021] [Accepted: 05/20/2021] [Indexed: 12/24/2022] Open
Abstract
Cabozantinib (CAB) is a receptor tyrosine kinase inhibitor approved for the treatment of several cancer types. Enterohepatic recirculation (EHC) of the substance is assumed but has not been further investigated yet. CAB is mainly metabolized via CYP3A4 and is susceptible for drug-drug interactions (DDI). The goal of this work was to develop a physiologically based pharmacokinetic (PBPK) model to investigate EHC, to simulate DDI with Rifampin and to simulate subjects with hepatic impairment. The model was established using PK-Sim® and six human clinical studies. The inclusion of an EHC process into the model led to the most accurate description of the pharmacokinetic behavior of CAB. The model was able to predict plasma concentrations with low bias and good precision. Ninety-seven percent of all simulated plasma concentrations fell within 2-fold of the corresponding concentration observed. Maximum plasma concentration (Cmax) and area under the curve (AUC) were predicted correctly (predicted/observed ratio of 0.9-1.2 for AUC and 0.8-1.1 for Cmax). DDI with Rifampin led to a reduction in predicted AUC by 77%. Several physiological parameters were adapted to simulate hepatic impairment correctly. This is the first CAB model used to simulate DDI with Rifampin and hepatic impairment including EHC, which can serve as a starting point for further simulations with regard to special populations.
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Chan KL, Varughese N, Jones PM, Zwick DL, Rajaram V, Lee M, Ramirez CM. A Case of Dubin-Johnson Syndrome Presenting as Neonatal Cholestasis With Paucity of Interlobular Bile Ducts. Pediatr Dev Pathol 2021; 24:154-158. [PMID: 33470920 DOI: 10.1177/1093526620980577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Dubin-Johnson syndrome (DJS) is a rare autosomal recessive disorder that typically manifests in young adulthood as jaundice with conjugated hyperbilirubinemia. We report a case presenting as neonatal cholestasis with the unexpected histologic finding of paucity of interlobular bile ducts, a feature that is not typically seen in DJS. The diagnosis was confirmed by absent canalicular multidrug-resistance-associated protein 2 (MRP2) immunohistochemical staining on liver biopsy tissue and molecular genetic testing that demonstrated heterozygous mutations in the ATP-Binding Cassette Subfamily C Member 2 (ABCC2) gene, including a novel missense mutation. This report describes a case of DJS with atypical clinicopathologic findings and suggests that DJS should be considered in patients with neonatal cholestasis and bile duct paucity.
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Affiliation(s)
- Kara L Chan
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Natasha Varughese
- Department of Pediatrics, UT Southwestern Medical Center/Children's Medical Center, Dallas, Texas
| | - Patricia M Jones
- Department of Pathology, UT Southwestern Medical Center/Children's Medical Center, Dallas, Texas
| | - David L Zwick
- Department of Pathology, UT Southwestern Medical Center/Children's Medical Center, Dallas, Texas
| | - Veena Rajaram
- Department of Pathology, UT Southwestern Medical Center/Children's Medical Center, Dallas, Texas
| | - Michael Lee
- Department of Pediatrics, UT Southwestern Medical Center/Children's Medical Center, Dallas, Texas
| | - Charina M Ramirez
- Department of Pediatrics, UT Southwestern Medical Center/Children's Medical Center, Dallas, Texas
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Harnisch LO, Moerer O. The Specific Bile Acid Profile of Shock: A Hypothesis Generating Appraisal of the Literature. J Clin Med 2020; 9:E3844. [PMID: 33256244 PMCID: PMC7761042 DOI: 10.3390/jcm9123844] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 11/21/2020] [Accepted: 11/25/2020] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Bile acid synthesis and regulation of metabolism are tightly regulated. In critical illness, these regulations are impaired. Consequently, the physiologic bile acid pattern in serum becomes disturbed and a disease-specific bile acid profile seems to become evident. METHODS A literature review was performed and trials reporting the broken-down bile acid pattern were condensed with regard to percent differences in bile acid profiles of defined diseases compared to a human control. RESULTS Ten articles were identified. Most of the studied bile acid profiles differ statistically significant between disease states, furthermore, neither of the reported disease entities show the same broken-down pattern of individual bile acids. Deoxycholic acid (DCA) was found to be decreased in almost all diseases, except for the two shock-states investigated (cardiogenic shock, septic shock) where it was elevated by about 100% compared to the control. Moreover, the pattern of both examined shock-states are very similar, rendering a specific shock-pattern possible, that we argue could eventually maintain or even worsen the pathological state. CONCLUSION The specific broken-down bile acid profile of defined diseases might aid in gaining insight into the body's adaptive reaction and the differential diagnosis, as well as in the therapy of disease states in the early course of the disease.
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Affiliation(s)
- Lars-Olav Harnisch
- Department of Anesthesiology, University of Göttingen, 37075 Göttingen, Germany;
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10
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Ali Y, Shams T, Wang K, Cheng Z, Li Y, Shu W, Bao X, Zhu L, Murray M, Zhou F. The involvement of human organic anion transporting polypeptides (OATPs) in drug-herb/food interactions. Chin Med 2020; 15:71. [PMID: 32670395 PMCID: PMC7346646 DOI: 10.1186/s13020-020-00351-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 07/03/2020] [Indexed: 02/08/2023] Open
Abstract
Organic anion transporting polypeptides (OATPs) are important transporter proteins that are expressed at the plasma membrane of cells, where they mediate the influx of endogenous and exogenous substances including hormones, natural compounds and many clinically important drugs. OATP1A2, OATP2B1, OATP1B1 and OATP1B3 are the most important OATP isoforms and influence the pharmacokinetic performance of drugs. These OATPs are highly expressed in the kidney, intestine and liver, where they determine the distribution of drugs to these tissues. Herbal medicines are increasingly popular for their potential health benefits. Humans are also exposed to many natural compounds in fruits, vegetables and other food sources. In consequence, the consumption of herbal medicines or food sources together with a range of important drugs can result in drug-herb/food interactions via competing specific OATPs. Such interactions may lead to adverse clinical outcomes and unexpected toxicities of drug therapies. This review summarises the drug-herb/food interactions of drugs and chemicals that are present in herbal medicines and/or food in relation to human OATPs. This information can contribute to improving clinical outcomes and avoiding unexpected toxicities of drug therapies in patients.
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Affiliation(s)
- Youmna Ali
- Faculty of Medicine and Health, Sydney Pharmacy School, The University of Sydney, Camperdown, NSW 2006 Australia
| | - Tahiatul Shams
- Faculty of Medicine and Health, Sydney Pharmacy School, The University of Sydney, Camperdown, NSW 2006 Australia
| | - Ke Wang
- Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu China
| | - Zhengqi Cheng
- Faculty of Medicine and Health, Sydney Pharmacy School, The University of Sydney, Camperdown, NSW 2006 Australia
| | - Yue Li
- Faculty of Medicine and Health, Sydney Pharmacy School, The University of Sydney, Camperdown, NSW 2006 Australia
| | - Wenying Shu
- Faculty of Medicine and Health, Sydney Pharmacy School, The University of Sydney, Camperdown, NSW 2006 Australia.,Department of Pharmacy, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province 511400 China
| | - Xiaofeng Bao
- School of Pharmacy, Nantong University, Nantong, Jiangsu Province 226019 China
| | - Ling Zhu
- The University of Sydney, Save Sight Institute, Sydney, NSW 2000 Australia
| | - Michael Murray
- Faculty of Medicine and Health, Discipline of Pharmacology, The University of Sydney, Camperdown, NSW 2006 Australia
| | - Fanfan Zhou
- Faculty of Medicine and Health, Sydney Pharmacy School, The University of Sydney, Camperdown, NSW 2006 Australia
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11
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Ghanem CI, Manautou JE. Modulation of Hepatic MRP3/ABCC3 by Xenobiotics and Pathophysiological Conditions: Role in Drug Pharmacokinetics. Curr Med Chem 2019; 26:1185-1223. [PMID: 29473496 DOI: 10.2174/0929867325666180221142315] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Revised: 01/17/2018] [Accepted: 02/05/2018] [Indexed: 12/13/2022]
Abstract
Liver transporters play an important role in the pharmacokinetics and disposition of pharmaceuticals, environmental contaminants, and endogenous compounds. Among them, the family of ATP-Binding Cassette (ABC) transporters is the most important due to its role in the transport of endo- and xenobiotics. The ABCC sub-family is the largest one, consisting of 13 members that include the cystic fibrosis conductance regulator (CFTR/ABCC7); the sulfonylurea receptors (SUR1/ABCC8 and SUR2/ABCC9) and the multidrug resistanceassociated proteins (MRPs). The MRP-related proteins can collectively confer resistance to natural, synthetic drugs and their conjugated metabolites, including platinum-containing compounds, folate anti-metabolites, nucleoside and nucleotide analogs, among others. MRPs can be also catalogued into "long" (MRP1/ABCC1, -2/C2, -3/C3, -6/C6, and -7/C10) and "short" (MRP4/C4, -5/C5, -8/C11, -9/C12, and -10/C13) categories. While MRP2/ABCC2 is expressed in the canalicular pole of hepatocytes, all others are located in the basolateral membrane. In this review, we summarize information from studies examining the changes in expression and regulation of the basolateral hepatic transporter MPR3/ABCC3 by xenobiotics and during various pathophysiological conditions. We also focus, primarily, on the consequences of such changes in the pharmacokinetic, pharmacodynamic and/or toxicity of different drugs of clinical use transported by MRP3.
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Affiliation(s)
- Carolina I Ghanem
- Instituto de Investigaciones Farmacologicas (ININFA), Facultad de Farmacia y Bioquimica. CONICET. Universidad de Buenos Aires, Buenos Aires, Argentina.,Catedra de Fisiopatologia. Facultad de Farmacia y Bioquimica. Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Jose E Manautou
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, United States
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12
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Role of ERK1/2 in TNFα-induced internalization of Abcc2 in rat hepatocyte couplets. Biochem Pharmacol 2019; 164:311-320. [DOI: 10.1016/j.bcp.2019.04.024] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 04/22/2019] [Indexed: 01/10/2023]
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13
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Anselm V, Novikova S, Zgoda V. Re-adaption on Earth after Spaceflights Affects the Mouse Liver Proteome. Int J Mol Sci 2017; 18:E1763. [PMID: 28805685 PMCID: PMC5578152 DOI: 10.3390/ijms18081763] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Revised: 08/02/2017] [Accepted: 08/09/2017] [Indexed: 01/26/2023] Open
Abstract
Harsh environmental conditions including microgravity and radiation during prolonged spaceflights are known to alter hepatic metabolism. Our studies have focused on the analysis of possible changes in metabolic pathways in the livers of mice from spaceflight project "Bion-M 1". Mice experienced 30 days of spaceflight with and without an additional re-adaption period of seven days compared to control mice on Earth. To investigate mice livers we have performed proteomic profiling utilizing shotgun mass spectrometry followed by label-free quantification. Proteomic data analysis provided 12,206 unique peptides and 1,086 identified proteins. Label-free quantification using MaxQuant software followed by multiple sample statistical testing (ANOVA) revealed 218 up-regulated and 224 down-regulated proteins in the post-flight compared to the other groups. Proteins related to amino acid metabolism showed higher levels after re-adaption, which may indicate higher rates of gluconeogenesis. Members of the peroxisome proliferator-activated receptor pathway reconstitute their level after seven days based on a decreased level in comparison with the flight group, which indicates diminished liver lipotoxicity. Moreover, bile acid secretion may regenerate on Earth due to reconstitution of related transmembrane proteins and CYP superfamily proteins elevated levels seven days after the spaceflight. Thus, our study demonstrates reconstitution of pharmacological response and decreased liver lipotoxicity within seven days, whereas glucose uptake should be monitored due to alterations in gluconeogenesis.
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Affiliation(s)
- Viktoria Anselm
- Interfaculty Institute of Biochemistry (IFIB), Hoppe-Seyler-Straße 4, Tuebingen 72076.
| | - Svetlana Novikova
- Orekhovich Institute of Biomedical Chemistry of Russian Academy of Medical Sciences, Pogodinskaya 10, Moscow 119121.
| | - Victor Zgoda
- Orekhovich Institute of Biomedical Chemistry of Russian Academy of Medical Sciences, Pogodinskaya 10, Moscow 119121.
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14
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Xu D, You G. Loops and layers of post-translational modifications of drug transporters. Adv Drug Deliv Rev 2017; 116:37-44. [PMID: 27174152 DOI: 10.1016/j.addr.2016.05.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Accepted: 05/03/2016] [Indexed: 12/19/2022]
Abstract
Drug transporters encoded by solute carrier (SLC) family are distributed in multiple organs including kidney, liver, placenta, brain, and intestine, where they mediate the absorption, distribution, and excretion of a diverse array of environmental toxins and clinically important drugs. Alterations in the expression and function of these transporters play important roles in intra- and inter-individual variability of the therapeutic efficacy and the toxicity of many drugs. Consequently, the activity of these transporters must be highly regulated to carry out their normal functions. While it is clear that the regulation of these transporters tightly depends on genetic mechanisms, many studies have demonstrated that these transporters are the target of various post-translational modifications. This review article summarizes the recent advances in identifying the posttranslational modifications underlying the regulation of the drug transporters of SLC family. Such mechanisms are pivotal not only in physiological conditions, but also in diseases.
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15
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Murray M, Zhou F. Trafficking and other regulatory mechanisms for organic anion transporting polypeptides and organic anion transporters that modulate cellular drug and xenobiotic influx and that are dysregulated in disease. Br J Pharmacol 2017; 174:1908-1924. [PMID: 28299773 DOI: 10.1111/bph.13785] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Revised: 03/01/2017] [Accepted: 03/05/2017] [Indexed: 12/25/2022] Open
Abstract
Organic anion transporters (OATs) and organic anion-transporting polypeptides (OATPs), encoded by a number of solute carrier (SLC)22A and SLC organic anion (SLCO) genes, mediate the absorption and distribution of drugs and other xenobiotics. The regulation of OATs and OATPs is complex, comprising both transcriptional and post-translational mechanisms. Plasma membrane expression is required for cellular substrate influx by OATs/OATPs. Thus, interest in post-translational regulatory processes, including membrane targeting, endocytosis, recycling and degradation of transporter proteins, is increasing because these are critical for plasma membrane expression. After being synthesized, transporters undergo N-glycosylation in the endoplasmic reticulum and Golgi apparatus and are delivered to the plasma membrane by vesicular transport. Their expression at the cell surface is maintained by de novo synthesis and recycling, which occurs after clathrin- and/or caveolin-dependent endocytosis of existing protein. Several studies have shown that phosphorylation by signalling kinases is important for the internalization and recycling processes, although the transporter protein does not appear to be directly phosphorylated. After internalization, transporters that are targeted for degradation undergo ubiquitination, most likely on intracellular loop residues. Epigenetic mechanisms, including methylation of gene regulatory regions and transcription from alternate promoters, are also significant in the regulation of certain SLC22A/SLCO genes. The membrane expression of OATs/OATPs is dysregulated in disease, which affects drug efficacy and detoxification. Several transporters are expressed in the cytoplasmic subcompartment in disease states, which suggests that membrane targeting/internalization/recycling may be impaired. This article focuses on recent developments in OAT and OATP regulation, their dysregulation in disease and the significance for drug therapy.
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Affiliation(s)
- Michael Murray
- Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, NSW, 2006, Australia
| | - Fanfan Zhou
- Faculty of Pharmacy, The University of Sydney, NSW, 2006, Australia
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16
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Chen H, Huang X, Min J, Li W, Zhang R, Zhao W, Liu C, Yi L, Mi S, Wang N, Wang Q, Zhu C. Geniposidic acid protected against ANIT-induced hepatotoxity and acute intrahepatic cholestasis, due to Fxr-mediated regulation of Bsep and Mrp2. JOURNAL OF ETHNOPHARMACOLOGY 2016; 179:197-207. [PMID: 26723467 DOI: 10.1016/j.jep.2015.12.033] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Revised: 12/12/2015] [Accepted: 12/20/2015] [Indexed: 06/05/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Geniposidic acid (GPA) is the main constituent of Gardenia jasminoides Ellis (Rubiaceae), which has long been used to treat inflammation, jaundice and hepatic disorders. The cholagogic effect of Gardenia jasminoides Ellis (Rubiaceae) and GPA have been widely reported, but the underlying occurrence mechanism remains unclear. AIM OF THE STUDY This investigation was designed to evaluate the hepatoprotection effect and potential mechanisms of GPA derived from Gardenia jasminoides Ellis (Rubiaceae) on fighting against α-naphthylisothiocyanate (ANIT) caused liver injury with acute intrahepatic cholestasis. MATERIALS AND METHODS Sprague-Dawley (SD) rats were intragastrically (i.g.) administered with the GPA (100, 50 and 25mg/kg B.W. every 24h) for seven consecutive days, and then they were treated with ANIT (i.g. 65mg/kg once in the 5th day) which induced liver injury with acute intrahepatic cholestasis. Serum and bile biochemical analysis, bile flow rate and liver histopathology were measured to evaluate the protective effect of GPA fight against ANIT treatment. The protein and mRNA expression levels of farnesoid X receptor (Fxr), bile-salt export pump (Bsep), multidrug resistance associated protein2 (Mrp2), were evaluated to study the effect of liver protection about GPA against ANIT induced hepatotoxicity and underlying mechanisms. RESULTS Some abnormalities were observed on ANIT treated rats including weight loss, reduced food intake and hair turned yellow. Obtained results demonstrated that at dose 100 and 50mg/kg B.W. (P<0.01) and 25mg/kg B.W. (P<0.05) of GPA pretreated dramatically prevented ANIT induced decreased in bile flow rate. Compared with ANIT treated group, the results of bile biochemical parameters about total bile acid (TBA) was increased by GPA at groups with any dose (P<0.01), glutathione (GSH) was increased significantly at high dose (P<0.01) and medium dose (P<0.05), total bilirubin (TB) was increased at high and medium dose (P<0.05), direct bilirubin (DB) was only increased at high dose (P<0.01). Serum levels of glutamic-Oxalacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), γ-glutamyltranspeptidase (γ-GT), TB, DB and TBA in comparison with ANIT treated group (P<0.01) were reduced by GPA (between 100 and 50mg/kg B.W.) pretreatment. Histopathology of the liver tissue showed that pathological damages and hepatic portal area filled with bile were relieved after GPA pretreatment compared with ANIT treated group. The protein and mRNA expression of Fxr, Bsep and Mrp2 were decreased in ANIT treated group. On the contrary, the protein and mRNA of Fxr, Bsep and Mrp2 were up regulated significantly pretreatment by GPA at dose of high and medium groups. On protein level of Bsep and Mrp2 the result shown no statistical difference in GPA (25mg/kg B.W.), but it was not same shown in mRNA level. CONCLUSION The results of this investigation have demonstrated that the GPA exerts a dose dependent hepatoprotection effect on ANIT induced liver damage with acute intrahepatic cholestasis in rats, which may due to Fxr mediated regulation of bile transporters like Bsep and Mrp2.
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Affiliation(s)
- Hao Chen
- Institute of Clinical Pharmacology Biochemical Pharmacology Laboratory Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, Guangdong Province, PR China
| | - Xiaotao Huang
- Institute of Clinical Pharmacology Biochemical Pharmacology Laboratory Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, Guangdong Province, PR China
| | - Jianbin Min
- Institute of Clinical Pharmacology Biochemical Pharmacology Laboratory Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, Guangdong Province, PR China
| | - Weirong Li
- Institute of Clinical Pharmacology Biochemical Pharmacology Laboratory Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, Guangdong Province, PR China
| | - Rong Zhang
- Institute of Clinical Pharmacology Biochemical Pharmacology Laboratory Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, Guangdong Province, PR China
| | - Wei Zhao
- Institute of Clinical Pharmacology Biochemical Pharmacology Laboratory Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, Guangdong Province, PR China.
| | - Changhui Liu
- Institute of Clinical Pharmacology Biochemical Pharmacology Laboratory Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, Guangdong Province, PR China.
| | - Lang Yi
- Institute of Clinical Pharmacology Biochemical Pharmacology Laboratory Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, Guangdong Province, PR China
| | - Suiqing Mi
- Institute of Clinical Pharmacology Biochemical Pharmacology Laboratory Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, Guangdong Province, PR China
| | - Ningsheng Wang
- Institute of Clinical Pharmacology Biochemical Pharmacology Laboratory Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, Guangdong Province, PR China
| | - Qi Wang
- Institute of Clinical Pharmacology Biochemical Pharmacology Laboratory Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, Guangdong Province, PR China
| | - Chenchen Zhu
- Institute of Clinical Pharmacology Biochemical Pharmacology Laboratory Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, Guangdong Province, PR China
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17
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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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18
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Khurana V, Minocha M, Pal D, Mitra AK. Role of OATP-1B1 and/or OATP-1B3 in hepatic disposition of tyrosine kinase inhibitors. ACTA ACUST UNITED AC 2015; 29:179-90. [PMID: 24643910 DOI: 10.1515/dmdi-2013-0062] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Accepted: 02/12/2014] [Indexed: 11/15/2022]
Abstract
BACKGROUND The metabolism of tyrosine kinase inhibitors (TKIs) is mainly mediated via hepatic route, but the mechanism responsible for their hepatocellular accumulation is still unknown. This study was designed to understand the contribution of organic anion transporting polypeptides (OATPs) in the hepatic uptake of selected TKIs - pazopanib, canertinib, erlotinib, vandetanib and nilotinib. METHODS Michaelis-Menten (MM) kinetic parameters for TKIs were determined by concentration-dependent cellular accumulation of selected TKIs using Chinese hamster ovary cells - wild type as well as transfected with humanized OATP-1B1 and OATP-1B3 transporter proteins. RESULTS The MM constant (Km) values of OATP-1B1 for nilotinib and vandetanib are 10.14±1.91 and 2.72±0.25 μM, respectively, and Vmax values of OATP-1B1 for nilotinib and vandetanib were 6.95±0.47 and 75.95±1.99 nmol/mg protein per minute, respectively. Likewise, Km values of OATP-1B3 for canertinib, nilotinib and vandetanib were 12.18±3.32, 7.84±1.43 and 4.37±0.79 μM, respectively, and Vmax values of OATP-1B3 for canertinib, nilotinib and vandetanib were 15.34±1.59, 6.75±0.42 and 194.64±10.58 nmol/mg protein per minute, respectively. Canertinib did not exhibit any substrate specificity toward OATP-1B1. Also, erlotinib and pazopanib did not exhibit any substrate specificity toward OATP-1B1 and -1B3. CONCLUSIONS Because selected TKIs are the substrates of OATP-1B1 and -1B3 expressed in hepatic tissue, these compounds can be regarded as molecular targets for transporter-mediated drug-drug interactions (DDIs). Any alteration in the function of these hepatic OATPs might account for the pharmacokinetic variability of TKIs.
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19
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Kühn JP, Spoerl M, Nassif A, Mester M, Weitschies W, Siegmund W, Hosten N, Mensel B. Feasibility of gadoxetate disodium-enhanced MR cholangiography in chronic cholestatic biliary disease. Clin Radiol 2014; 69:1027-33. [PMID: 24957855 DOI: 10.1016/j.crad.2014.05.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Revised: 05/05/2014] [Accepted: 05/08/2014] [Indexed: 12/22/2022]
Abstract
AIM To investigate the feasibility of gadoxetate disodium-enhanced magnetic resonance (MR) cholangiography in chronic obstructive cholestatic biliary disease in the clinical setting. MATERIALS AND METHODS Twenty-three patients with dilated bile duct trees and ten volunteers underwent gadoxetate disodium-enhanced liver MR cholangiography and were enrolled in the present retrospective study. Gadoxetate disodium was given in a standardized manner as a bolus injection at a dose of 0.25 mmol/kg of body weight (0.1 ml/kg). Region of interest-based measurement of mean enhancement of the dilated bile ducts was performed in series before gadoxetate disodium administration and during hepatobiliary phases. RESULTS Direct comparison of mean bile duct enhancement during hepatobiliary phases in the clinical imaging window between healthy volunteers [4.7 ± 2.2 arbitrary units (au)] and patients with dilated bile ducts (0.1 ± 0.3 au) revealed significantly lower or absent enhancement in dilated bile ducts (p = 0.001). CONCLUSION Standard clinical gadoxetate disodium-enhanced MR cholangiography is not a reliable technique for the evaluation of the biliary trees, because of altered biliary gadoxetate disodium elimination in patients with chronic obstructive biliary diseases.
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Affiliation(s)
- J-P Kühn
- Department of Radiology and Neuroradiology, Ernst Moritz Arndt University Greifswald, Ferdinand-Sauerbruch-Straße NK, Greifswald, D-17475, Germany.
| | - M Spoerl
- Department of Radiology and Neuroradiology, Ernst Moritz Arndt University Greifswald, Ferdinand-Sauerbruch-Straße NK, Greifswald, D-17475, Germany
| | - A Nassif
- Department of Clinical Pharmacology, Ernst Moritz Arndt University Greifswald, Felix Hausdorff-Strasse 3, Greifswald, D-17475, Germany
| | - M Mester
- Department of Radiology and Neuroradiology, Ernst Moritz Arndt University Greifswald, Ferdinand-Sauerbruch-Straße NK, Greifswald, D-17475, Germany
| | - W Weitschies
- Department of Biopharmacy and Pharmaceutical Technology, Ernst Moritz Arndt University Greifswald, Felix Hausdorff-Strasse 3, Greifswald, D-17475, Germany
| | - W Siegmund
- Department of Clinical Pharmacology, Ernst Moritz Arndt University Greifswald, Felix Hausdorff-Strasse 3, Greifswald, D-17475, Germany
| | - N Hosten
- Department of Radiology and Neuroradiology, Ernst Moritz Arndt University Greifswald, Ferdinand-Sauerbruch-Straße NK, Greifswald, D-17475, Germany
| | - B Mensel
- Department of Radiology and Neuroradiology, Ernst Moritz Arndt University Greifswald, Ferdinand-Sauerbruch-Straße NK, Greifswald, D-17475, Germany
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Abstract
Bile is a unique and vital aqueous secretion of the liver that is formed by the hepatocyte and modified down stream by absorptive and secretory properties of the bile duct epithelium. Approximately 5% of bile consists of organic and inorganic solutes of considerable complexity. The bile-secretory unit consists of a canalicular network which is formed by the apical membrane of adjacent hepatocytes and sealed by tight junctions. The bile canaliculi (∼1 μm in diameter) conduct the flow of bile countercurrent to the direction of portal blood flow and connect with the canal of Hering and bile ducts which progressively increase in diameter and complexity prior to the entry of bile into the gallbladder, common bile duct, and intestine. Canalicular bile secretion is determined by both bile salt-dependent and independent transport systems which are localized at the apical membrane of the hepatocyte and largely consist of a series of adenosine triphosphate-binding cassette transport proteins that function as export pumps for bile salts and other organic solutes. These transporters create osmotic gradients within the bile canalicular lumen that provide the driving force for movement of fluid into the lumen via aquaporins. Species vary with respect to the relative amounts of bile salt-dependent and independent canalicular flow and cholangiocyte secretion which is highly regulated by hormones, second messengers, and signal transduction pathways. Most determinants of bile secretion are now characterized at the molecular level in animal models and in man. Genetic mutations serve to illuminate many of their functions.
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Affiliation(s)
- James L Boyer
- Department of Medicine and Liver Center, Yale University School of Medicine, New Haven, Connecticut, USA.
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21
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Pollheimer MJ, Fickert P, Stieger B. Chronic cholestatic liver diseases: clues from histopathology for pathogenesis. Mol Aspects Med 2013; 37:35-56. [PMID: 24141039 DOI: 10.1016/j.mam.2013.10.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2013] [Revised: 10/04/2013] [Accepted: 10/07/2013] [Indexed: 02/06/2023]
Abstract
Chronic cholestatic liver diseases include fibrosing cholangiopathies such as primary biliary cirrhosis or primary sclerosing cholangitis. These and related cholangiopathies clearly display pathologies associated with (auto)immunologic processes. As the cholangiocyte's apical membrane is exposed to the toxic actions of the bile fluid, the interaction of bile with cholangiocytes and the biliary tree in general must be considered to completely understand the pathogenesis of cholangiopathies. While the molecular processes involved in the hepatocellular formation of bile are well understood in both normal and pathophysiologic conditions, those in the bile ducts of normal liver and in livers with cholangiopathies lag behind. This survey highlights key mechanisms known to date that are important for the formation of bile by hepatocytes and its modification by the biliary tree. It also delineates the clinical pathophysiologic findings for cholangiopathies and puts them in perspective with current experimental models to reveal the pathogenesis of cholangiopathies and develop novel therapeutic approaches.
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Affiliation(s)
- Marion J Pollheimer
- Division of Gastroenterology and Hepatology, Laboratory of Experimental and Molecular Hepatology, Department of Internal Medicine, Medical University of Graz, Austria; Institute of Pathology, Medical University of Graz, Austria
| | - Peter Fickert
- Division of Gastroenterology and Hepatology, Laboratory of Experimental and Molecular Hepatology, Department of Internal Medicine, Medical University of Graz, Austria; Institute of Pathology, Medical University of Graz, Austria.
| | - Bruno Stieger
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland.
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22
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Sticova E, Jirsa M. New insights in bilirubin metabolism and their clinical implications. World J Gastroenterol 2013; 19:6398-6407. [PMID: 24151358 PMCID: PMC3801310 DOI: 10.3748/wjg.v19.i38.6398] [Citation(s) in RCA: 123] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2013] [Revised: 07/18/2013] [Accepted: 08/09/2013] [Indexed: 02/06/2023] Open
Abstract
Bilirubin, a major end product of heme breakdown, is an important constituent of bile, responsible for its characteristic colour. Over recent decades, our understanding of bilirubin metabolism has expanded along with the processes of elimination of other endogenous and exogenous anionic substrates, mediated by the action of multiple transport systems at the sinusoidal and canalicular membrane of hepatocytes. Several inherited disorders characterised by impaired bilirubin conjugation (Crigler-Najjar syndrome type I and type II, Gilbert syndrome) or transport (Dubin-Johnson and Rotor syndrome) result in various degrees of hyperbilirubinemia of either the predominantly unconjugated or predominantly conjugated type. Moreover, disrupted regulation of hepatobiliary transport systems can explain jaundice in many acquired liver disorders. In this review, we discuss the recent data on liver bilirubin handling based on the discovery of the molecular basis of Rotor syndrome. The data show that a substantial fraction of bilirubin conjugates is primarily secreted by MRP3 at the sinusoidal membrane into the blood, from where they are subsequently reuptaken by sinusoidal membrane-bound organic anion transporting polypeptides OATP1B1 and OATP1B3. OATP1B proteins are also responsible for liver clearance of bilirubin conjugated in splanchnic organs, such as the intestine and kidney, and for a number of endogenous compounds, xenobiotics and drugs. Absence of one or both OATP1B proteins thus may have serious impact on toxicity of commonly used drugs cleared by this system such as statins, sartans, methotrexate or rifampicin. The liver-blood cycling of conjugated bilirubin is impaired in cholestatic and parenchymal liver diseases and this impairment most likely contributes to jaundice accompanying these disorders.
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Roth M, Obaidat A, Hagenbuch B. OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies. Br J Pharmacol 2012; 165:1260-87. [PMID: 22013971 DOI: 10.1111/j.1476-5381.2011.01724.x] [Citation(s) in RCA: 574] [Impact Index Per Article: 44.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The human organic anion and cation transporters are classified within two SLC superfamilies. Superfamily SLCO (formerly SLC21A) consists of organic anion transporting polypeptides (OATPs), while the organic anion transporters (OATs) and the organic cation transporters (OCTs) are classified in the SLC22A superfamily. Individual members of each superfamily are expressed in essentially every epithelium throughout the body, where they play a significant role in drug absorption, distribution and elimination. Substrates of OATPs are mainly large hydrophobic organic anions, while OATs transport smaller and more hydrophilic organic anions and OCTs transport organic cations. In addition to endogenous substrates, such as steroids, hormones and neurotransmitters, numerous drugs and other xenobiotics are transported by these proteins, including statins, antivirals, antibiotics and anticancer drugs. Expression of OATPs, OATs and OCTs can be regulated at the protein or transcriptional level and appears to vary within each family by both protein and tissue type. All three superfamilies consist of 12 transmembrane domain proteins that have intracellular termini. Although no crystal structures have yet been determined, combinations of homology modelling and mutation experiments have been used to explore the mechanism of substrate recognition and transport. Several polymorphisms identified in members of these superfamilies have been shown to affect pharmacokinetics of their drug substrates, confirming the importance of these drug transporters for efficient pharmacological therapy. This review, unlike other reviews that focus on a single transporter family, briefly summarizes the current knowledge of all the functionally characterized human organic anion and cation drug uptake transporters of the SLCO and the SLC22A superfamilies.
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Affiliation(s)
- Megan Roth
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, USA
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Hope TA, Doherty A, Fu Y, Aslam R, Qayyum A, Brasch RC. Gadolinium accumulation and fibrosis in the liver after administration of gadoxetate disodium in a rat model of active hepatic fibrosis. Radiology 2012; 264:423-7. [PMID: 22570507 DOI: 10.1148/radiol.12112453] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
PURPOSE To evaluate the effect of gadoxetate disodium on fibrosis in a rat model of active hepatic fibrosis. MATERIALS AND METHODS The local committee for animal research approved this study. Hepatic fibrosis was induced during 12 weeks of intraperitoneal injection of carbon tetrachloride (CCl(4)). Gadoxetate disodium was administered at 10 mmol/kg for 5 consecutive days starting after the final dose of CCl(4) (clinical dose of gadoxetate disodium is 0.25 mmol/kg). Three groups of Sprague-Dawley rats were studied. Group 1 consisted of six rats treated only with gadoxetate disodium, group 2 consisted of nine rats treated only with CCl(4), and group 3 consisted of nine rats treated with both gadoxetate disodium and CCl(4). Seven days after the final injection of gadoxetate disodium, the rats were sacrificed, and histologic findings and gadolinium deposition in the liver were examined. Fibrosis stage and gadolinium deposition were compared by using the Mann-Whitney test and Student t test. RESULTS Fibrosis grading in groups 2 and 3 did not differ significantly (mean Batts-Ludwig fibrosis stage in group 2 was 2.67 and in group 3 was 2.78, P = .70; mean Ishak fibrosis stage in group 2 was 3.89 and in group 3 was 4.11, P = .71). Gadolinium deposition in the liver was slightly increased in group 3 in comparison to group 1 (3.2 ppm versus 4.0 ppm, P = .01), although this reversed when corrected as a percentage of total injected dose (0.022% versus 0.017%, P = .003). CONCLUSION The high-dose administration of gadoxetate disodium in the setting of active hepatic fibrosis was not associated with increased fibrosis, suggesting that gadoxetate disodium does not incite a nephrogenic systemic fibrosis-like fibrotic change in the setting of active hepatic inflammation.
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Affiliation(s)
- Thomas A Hope
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94143, USA.
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Abstract
The secretion of bile normally depends on the function of a number of membrane transport systems in hepatocytes and cholangiocytes. The transport of solutes from the blood to the bile is driven by transport systems in the plasma membrane of the basolateral and canalicular surfaces of the hepatocytes. In cholestatic animal models, the expression of hepatobiliary transporters changes in response to functional impairment of the efflux of bile salts and various organic anions. In recent years, several studies have led to an improved understanding of the function and regulation of hepatobiliary transport systems in patients with primary biliary cirrhosis (PBC). This review focuses on the adaptations in hepatobiliary transporters in PBC patients.
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Affiliation(s)
- Yasuaki Takeyama
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
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Cytoprotective properties of rifampicin are related to the regulation of detoxification system and bile acid transporter expression during hepatocellular injury induced by hydrophobic bile acids. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2011; 18:740-50. [PMID: 21526375 DOI: 10.1007/s00534-011-0396-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
BACKGROUND/PURPOSE Rifampicin has been used for the treatment of patients with jaundice and pruritus. This study evaluated the effect of rifampicin on the expression of different detoxification systems and bile acid transporters during in-vivo and in-vitro experimental models of cholestasis. METHODS Rifampicin was administered to glycochenodeoxycholic acid (GCDCA)-treated human hepatocytes and bile duct-obstructed rats. Different parameters related to cell death, and the expression of phase I and II drug metabolizing enzymes (DME) and bile acid transporters were determined. RESULTS The induction of hepatocellular injury induced by cholestasis was associated with a reduction in cytochrome P4503A4 (CYP3A4), CYP7A1, and UDP-glucuronosyltransferase 2B4 (UGT2B4) expression, as well as an increase in import (Na(+)-taurocholate co-transporting polypeptide, NTCP) system expression. The beneficial properties of rifampicin were associated with an increase in DME and export bile acid systems (multidrug resistance-associated protein 4, MRP4, and bile acid export pump to bile duct, BSEP) expression, as well as a reduction in NTCP expression. CONCLUSIONS The beneficial effect of rifampicin in cholestasis is associated with an increase in DME expression involved in toxic, bile acid and cholesterol metabolism, as well as a reduction in the bile acid importing system in hepatocytes.
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Pollheimer MJ, Halilbasic E, Fickert P, Trauner M. Pathogenesis of primary sclerosing cholangitis. Best Pract Res Clin Gastroenterol 2011; 25:727-39. [PMID: 22117638 PMCID: PMC3236286 DOI: 10.1016/j.bpg.2011.10.009] [Citation(s) in RCA: 94] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2011] [Accepted: 10/25/2011] [Indexed: 01/31/2023]
Abstract
Primary sclerosing cholangitis (PSC) represents a chronic cholestatic liver disease with fibroobliterative sclerosis of intra- and/or extrahepatic bile ducts, eventually leading to biliary cirrhosis. The association with human leukocyte antigen (HLA) and non-HLA haplotypes and the presence of autoantibodies in sera of PSC patients support a crucial role for immune-mediated mechanisms in the initiation and progression of PSC. The strong clinical association between PSC and inflammatory bowel diseases led to intriguing pathogenetic concepts, in which the inflamed gut with translocation of bacterial products and homing of gut-primed memory T lymphocytes via aberrantly expressed adhesion molecules plays a fundamental role. Genetically or chemically modified bile composition was shown to induce sclerosing cholangitis and liver fibrosis in a number of animal models ("toxic bile concept"). The potential role of vascular injury with ischemia of bile duct epithelium cells in the development of sclerosing cholangitis is supported by animal models of endothelial cell injury showing close morphological similarities with human PSC.
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Affiliation(s)
- Marion J. Pollheimer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria
| | - Emina Halilbasic
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Peter Fickert
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria,Corresponding author. Tel.:+43 (0) 1 40400 4741; fax: +43 (0) 1 40400 4735.
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Terui K, Saito T, Hishiki T, Sato Y, Mitsunaga T, Yoshida H. Hepatic expression of multidrug resistance protein 2 in biliary atresia. COMPARATIVE HEPATOLOGY 2011; 10:6. [PMID: 21813008 PMCID: PMC3161838 DOI: 10.1186/1476-5926-10-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/14/2011] [Accepted: 08/03/2011] [Indexed: 11/10/2022]
Abstract
BACKGROUND Biliary atresia (BA) is an idiopathic inflammatory obliterative cholangiopathy of neonates, leading to progressive biliary cirrhosis. Hepatoportoenterostomy (Kasai procedure) can cure jaundice in 30% to 80% of patients. Postoperative clearance of jaundice is one of the most important factors influencing long-term outcomes of BA patients. Multidrug resistance protein 2 (MRP2) is one of the canalicular export pumps located in hepatocytes; it exports organic anions and their conjugates (e.g., bilirubin) into bile canaliculus. Although MRP2 is an essential transporter for the excretion of bilirubin, its role in the clinical course of BA patients is unclear. The present study investigated the relationship between hepatic MRP2 expression and clinical course in BA patients, with particular emphasis in curing jaundice after hepatoportoenterostomy. RESULTS No significant differences in hepatic MRP2 expression level were observed between BA and controls groups. There was no correlation between MRP2 expression and age at time of surgery in BA and control groups. In BA patients, MRP2 expression level in the jaundice and jaundice-free group did not differ significantly (2.0 × 10-4 vs 3.1 × 10-4, p = 0.094). Although the serum level of total bilirubin just before surgery did not correlate with MRP2 expression level (rs = 0.031, p = 0.914), the serum level of total bilirubin measured at 2 weeks (rs = -0.569, p = 0.034) and 4 weeks after surgery (rs = -0.620, p = 0.018) were significantly correlated with MRP2 expression level. Furthermore, MRP2 expression level was inversely correlated with ratio of change in serum total bilirubin level over 4 weeks (rs = -0.676, p = 0.008), which represents the serum bilirubin level measured at 4 weeks after surgery divided by value just before surgery. There was no correlation between expression level of MRP2 and nuclear receptors, such as retinoid × receptor α, farnesoid × receptor, pregnane × receptor, or constitutive androstane receptor. CONCLUSIONS Hepatic MRP2 expression level was associated with postoperative clearance of jaundice in BA patients, at least within 1 month after hepatoportoenterostomy. This finding suggests that not only morphological appearance of the liver tissue but also the biological status of hepatocytes is important for BA pathophysiology.
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Affiliation(s)
- Keita Terui
- Department of Pediatric Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Takeshi Saito
- Department of Pediatric Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tomoro Hishiki
- Department of Pediatric Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yoshiharu Sato
- Department of Pediatric Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tetsuya Mitsunaga
- Department of Pediatric Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hideo Yoshida
- Department of Pediatric Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
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OATP 1B1/1B3 expression in hepatocellular carcinomas treated with orthotopic liver transplantation. Virchows Arch 2011; 459:141-6. [DOI: 10.1007/s00428-011-1099-5] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2011] [Revised: 05/16/2011] [Accepted: 05/23/2011] [Indexed: 12/14/2022]
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Gu X, Manautou JE. Regulation of hepatic ABCC transporters by xenobiotics and in disease states. Drug Metab Rev 2010; 42:482-538. [PMID: 20233023 DOI: 10.3109/03602531003654915] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
The subfamily of ABCC transporters consists of 13 members in mammals, including the multidrug resistance-associated proteins (MRPs), sulfonylurea receptors (SURs), and the cystic fibrosis transmembrane conductance regulator (CFTR). These proteins play roles in chemical detoxification, disposition, and normal cell physiology. ABCC transporters are expressed differentially in the liver and are regulated at the transcription and translation level. Their expression and function are also controlled by post-translational modification and membrane-trafficking events. These processes are tightly regulated. Information about alterations in the expression of hepatobiliary ABCC transporters could provide important insights into the pathogenesis of diseases and disposition of xenobiotics. In this review, we describe the regulation of hepatic ABCC transporters in humans and rodents by a variety of xenobiotics, under disease states and in genetically modified animal models deficient in transcription factors, transporters, and cell-signaling molecules.
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Affiliation(s)
- Xinsheng Gu
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, 06269, USA
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Zollner G, Wagner M, Trauner M. Nuclear receptors as drug targets in cholestasis and drug-induced hepatotoxicity. Pharmacol Ther 2010; 126:228-43. [PMID: 20388526 DOI: 10.1016/j.pharmthera.2010.03.005] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2010] [Accepted: 03/24/2010] [Indexed: 01/04/2023]
Abstract
Nuclear receptors are key regulators of various processes including reproduction, development, and metabolism of xeno- and endobiotics such as bile acids and drugs. Research in the last two decades provided researchers and clinicians with a detailed understanding of the regulation of these processes and, most importantly, also prompted the development of novel drugs specifically targeting nuclear receptors for the treatment of a variety of diseases. Some nuclear receptor agonists are already used in daily clinical practice but many more are currently designed or tested for the treatment of diabetes, dyslipidemia, fatty liver disease, cancer, drug hepatotoxicity and cholestasis. The hydrophilic bile acid ursodeoxycholic acid is currently the only available drug to treat cholestasis but its efficacy is limited. Therefore, development of novel treatments represents a major goal for both pharmaceutical industry and academic researchers. Targeting nuclear receptors in cholestasis is an intriguing approach since these receptors are critically involved in regulation of bile acid homeostasis. This review will discuss the general role of nuclear receptors in regulation of transporters and other enzymes maintaining bile acid homeostasis and will review the role of individual receptors as therapeutic targets. In addition, the central role of nuclear receptors and other transcription factors such as the aryl hydrocarbon receptor (AhR) and the nuclear factor-E2-related factor (Nrf2) in mediating drug disposition and their potential therapeutic role in drug-induced liver disease will be covered.
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Affiliation(s)
- Gernot Zollner
- Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University Graz, Auenbruggerplatz 15, A-8036 Graz, Austria
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Abstract
Hepatobiliary transport systems are essential for the uptake and excretion of a variety of compounds including bile acids. Disruption and dysregulation of this excretory pathway result in cholestasis, leading to the intrahepatic accumulation of bile acids and other toxic compounds with progression of liver pathology. Cholestasis induced by inflammation is a common complication in patients with extrahepatic infections or inflammatory processes, generally referred to as sepsis-associated cholestasis. Microbial products, including endotoxin, induce signaling pathways within hepatocytes either directly, or through activation of proinflammatory cytokines, leading to rapid and profound reductions in bile flow. The expression and function of key hepatobiliary transporters are suppressed in response to inflammatory signaling. These proinflammatory signaling cascades lead to repressed expression and activity of a large number of nuclear transcriptional regulators, many of which are essential for maintenance of hepatobiliary transporter gene expression. Interestingly, recently discovered molecular crosstalk between bile acid activated nuclear receptors and proinflammatory nuclear mediators may provide new means of understanding adaptive processes within liver. Inflammation-induced cholestasis and the effects of retained molecules in cholestasis on inflammatory signals are interwoven in the liver, providing potential opportunities for research and therapeutics.
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Abstract
Recent progress in basic research has enhanced our understanding of the molecular mechanisms of normal bile secretion and their alterations in cholestasis. Genetic transporter variants contribute to an entire spectrum of cholestatic liver diseases and can cause hereditary cholestatic syndromes or determine susceptibility and disease progression in acquired cholestatic disorders. Cholestasis is associated with complex transcriptional and post-transcriptional alterations of hepatobiliary transporters and enzymes participating in bile formation. Ligand-activated nuclear receptors for bile acids and other biliary compounds play a key role in the regulation of genes required for bile formation. Pharmacological interventions in cholestasis may aim at modulating such novel regulatory pathways. This review will summarize the principles of molecular alterations in cholestasis and will give an overview of potential clinical implications.
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Affiliation(s)
- Martin Wagner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Laboratory of Experimental and Molecular Hepatology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria
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Stahl S, Davies MR, Cook DI, Graham MJ. Nuclear hormone receptor-dependent regulation of hepatic transporters and their role in the adaptive response in cholestasis. Xenobiotica 2008; 38:725-77. [DOI: 10.1080/00498250802105593] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Hepatocyte-specific ablation of Foxa2 alters bile acid homeostasis and results in endoplasmic reticulum stress. Nat Med 2008; 14:828-36. [PMID: 18660816 DOI: 10.1038/nm.1853] [Citation(s) in RCA: 154] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2008] [Accepted: 06/30/2008] [Indexed: 01/16/2023]
Abstract
Production of bile by the liver is crucial for the absorption of lipophilic nutrients. Dysregulation of bile acid homeostasis can lead to cholestatic liver disease and endoplasmic reticulum (ER) stress. We show by global location analysis ('ChIP-on-chip') and cell type-specific gene ablation that the winged helix transcription factor Foxa2 is required for normal bile acid homeostasis. As suggested by the location analysis, deletion of Foxa2 in hepatocytes in mice using the Cre-lox system leads to decreased transcription of genes encoding bile acid transporters on both the basolateral and canalicular membranes, resulting in intrahepatic cholestasis. Foxa2-deficient mice are strikingly sensitive to a diet containing cholic acid, which results in toxic accumulation of hepatic bile salts, ER stress and liver injury. In addition, we show that expression of FOXA2 is markedly decreased in liver samples from individuals with different cholestatic syndromes, suggesting that reduced FOXA2 abundance could exacerbate the injury.
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Hepatocellular transport in acquired cholestasis: new insights into functional, regulatory and therapeutic aspects. Clin Sci (Lond) 2008; 114:567-88. [PMID: 18377365 DOI: 10.1042/cs20070227] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The recent overwhelming advances in molecular and cell biology have added enormously to our understanding of the physiological processes involved in bile formation and, by extension, to our comprehension of the consequences of their alteration in cholestatic hepatopathies. The present review addresses in detail this new information by summarizing a number of recent experimental findings on the structural, functional and regulatory aspects of hepatocellular transporter function in acquired cholestasis. This comprises (i) a short overview of the physiological mechanisms of bile secretion, including the nature of the transporters involved and their role in bile formation; (ii) the changes induced by nuclear receptors and hepatocyte-enriched transcription factors in the constitutive expression of hepatocellular transporters in cholestasis, either explaining the primary biliary failure or resulting from a secondary adaptive response; (iii) the post-transcriptional changes in transporter function and localization in cholestasis, including a description of the subcellular structures putatively engaged in the endocytic internalization of canalicular transporters and the involvement of signalling cascades in this effect; and (iv) a discussion on how this new information has contributed to the understanding of the mechanism by which anticholestatic agents exert their beneficial effects, or the manner in which it has helped the design of new successful therapeutic approaches to cholestatic liver diseases.
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Abstract
This article gives an overview of the molecular and cellular mechanisms of cholestasis. Topics reviewed include the pathomechanisms of hereditary cholestasis syndromes, such as progressive familial intrahepatic cholestasis, and hepatocellular transporter defects encountered in various acquired cholestatic disorders, such as intrahepatic cholestasis of pregnancy, drug-induced cholestasis, inflammatory cholestasis, primary sclerosing cholangitis, and primary biliary cirrhosis. In addition, current concepts regarding adaptive hepatocellular mechanisms counteracting cholestatic liver damage are discussed.
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Affiliation(s)
- Gernot Zollner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Laboratory of Experimental and Molecular Hepatology, Medical University of Graz, Auenbruggerplatz 15, A-8036 Graz, Austria
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Hepatocyte growth factor increases uptake of estradiol 17β-d-glucuronide and Oatp1 protein level in rat hepatocytes. Eur J Pharmacol 2008; 580:19-26. [DOI: 10.1016/j.ejphar.2007.10.041] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2007] [Revised: 10/12/2007] [Accepted: 10/16/2007] [Indexed: 02/08/2023]
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Furihata T, Satoh T, Yamamoto N, Kobayashi K, Chiba K. Hepatocyte nuclear factor 1 alpha is a factor responsible for the interindividual variation of OATP1B1 mRNA levels in adult Japanese livers. Pharm Res 2007; 24:2327-32. [PMID: 17932728 DOI: 10.1007/s11095-007-9458-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2007] [Accepted: 09/10/2007] [Indexed: 11/29/2022]
Abstract
PURPOSE The aim of the present study was to clarify the factors responsible for interindividual variability of organic anion transporting polypeptide (OATP, gene symbol SLCO) 1B1 mRNA expression level in the human liver. MATERIALS AND METHODS OATP1B1 mRNA expression levels were determined by real-time PCR in 31 human liver samples. The results were analyzed in relation to a single nucleotide polymorphism (-11187G>A) located in the promoter region and levels of hepatocyte nuclear factor (HNF) 1alpha mRNA. RESULTS There was a 4.9-fold interindividual variability of OATP1B1 mRNA expression level in the livers analyzed, which was not associated with -11187G>A polymorphism. Accordingly, the -11187G>A polymorphism did not alter the SLCO1B1 gene promoter activity in luciferase assays. On the other hand, OATP1B1 mRNA levels showed a significant correlation with HNF1alpha mRNA levels (r=0.83, P<0.0001). This correlation was consistent with the results of luciferase assays and chromatin immunoprecipitation assays showing functional interaction between HNF1alpha and SLCO1B1 gene promoter. CONCLUSIONS Our results suggest that HNF1alpha is an essential regulator of OATP1B1 mRNA expression and thus the level of HNF1alpha expression is one of the major determinants of interindividual variability in OATP1B1 mRNA expression.
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Affiliation(s)
- Tomomi Furihata
- Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8675, Japan.
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Zollner G, Wagner M, Fickert P, Silbert D, Gumhold J, Zatloukal K, Denk H, Trauner M. Expression of bile acid synthesis and detoxification enzymes and the alternative bile acid efflux pump MRP4 in patients with primary biliary cirrhosis. Liver Int 2007; 27:920-9. [PMID: 17696930 DOI: 10.1111/j.1478-3231.2007.01506.x] [Citation(s) in RCA: 96] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND Bile acid synthesis, transport and metabolism are markedly altered in experimental cholestasis. Whether such coordinated regulation exists in human cholestatic diseases is unclear. We therefore investigated expression of genes for bile acid synthesis, detoxification and alternative basolateral export and regulatory nuclear factors in primary biliary cirrhosis (PBC). MATERIAL/METHODS Hepatic CYP7A1, CYP27A1, CYP8B1 (bile acid synthesis), CYP3A4 (hydroxylation), SULT2A1 (sulphation), UGT2B4/2B7 (glucuronidation), MRP4 (basolateral export), farnesoid X receptor (FXR), retinoid X receptor (RXR), short heterodimer partner (SHP), hepatocyte nuclear factor 1alpha (HNF1alpha) and HNF4alpha expression was determined in 11 patients with late-stage PBC and this was compared with non-cholestatic controls. RESULTS CYP7A1 mRNA was repressed in PBC to 10-20% of controls, while CYP27 and CYP8B1 mRNA remained unchanged. SULT2A1, UGT2B4/2B7 and CYP3A4 mRNA levels were unaltered or only mildly reduced in PBC. MRP4 protein levels were induced three-fold in PBC, whereas mRNA levels remained unchanged. Expression levels of FXR, RXR, SHP, PXR, CAR, HNF1alpha and HNF4alpha were moderately reduced in PBC without reaching statistical significance. SUMMARY/CONCLUSIONS Repression of bile acid synthesis and induction of basolateral bile acid export may represent adaptive mechanisms to limit bile acid burden in chronic cholestasis. As these changes do not sufficiently counteract cholestatic liver damage, future therapeutic strategies should aim at stimulation of bile acid detoxification pathways.
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Affiliation(s)
- Gernot Zollner
- Laboratory of Experimental and Molecular Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
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Alrefai WA, Gill RK. Bile acid transporters: structure, function, regulation and pathophysiological implications. Pharm Res 2007; 24:1803-23. [PMID: 17404808 DOI: 10.1007/s11095-007-9289-1] [Citation(s) in RCA: 345] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2007] [Accepted: 02/28/2007] [Indexed: 12/11/2022]
Abstract
Specific transporters expressed in the liver and the intestine, play a critical role in driving the enterohepatic circulation of bile acids. By preserving a circulating pool of bile acids, an important factor influencing bile flow, these transporters are involved in maintaining bile acid and cholesterol homeostasis. Enterohepatic circulation of bile acids is fundamentally composed of two major processes: secretion from the liver and absorption from the intestine. In the hepatocytes, the vectorial transport of bile acids from blood to bile is ensured by Na+ taurocholate co-transporting peptide (NTCP) and organic anion transport polypeptides (OATPs). After binding to a cytosolic bile acid binding protein, bile acids are secreted into the canaliculus via ATP-dependent bile salt excretory pump (BSEP) and multi drug resistant proteins (MRPs). Bile acids are then delivered to the intestinal lumen through bile ducts where they emulsify dietary lipids and cholesterol to facilitate their absorption. Intestinal epithelial cells reabsorb the majority of the secreted bile acids through the apical sodium dependent bile acid transporter (ASBT) and sodium independent organic anion transporting peptide (OATPs). Cytosolic ileal bile acid binding protein (IBABP) mediates the transcellular movement of bile acids to the basolateral membrane across which they exit the cells via organic solute transporters (OST). An essential role of bile acid transporters is evident from the pathology associated with their genetic disruption or dysregulation of their function. Malfunctioning of hepatic and intestinal bile acid transporters is implicated in the pathophysiology of cholestatic liver disease and the depletion of circulating pool of bile acids, respectively. Extensive efforts have been recently made to enhance our understanding of the structure, function and regulation of the bile acid transporters and exploring new potential therapeutics to treat bile acid or cholesterol related diseases. This review will highlight current knowledge about structure, function and molecular characterization of bile acid transporters and discuss the implications of their defects in various hepatic and intestinal disorders.
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Affiliation(s)
- Waddah A Alrefai
- Section of Digestive Diseases and Nutrition, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
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Fukumoto K, Kikuchi S, Itoh N, Tamura A, Hata M, Yamagishi H, Tsukita S, Tsukita S. Effects of genetic backgrounds on hyperbilirubinemia in radixin-deficient mice due to different expression levels of Mrp3. Biochim Biophys Acta Mol Basis Dis 2007; 1772:298-306. [PMID: 17204408 DOI: 10.1016/j.bbadis.2006.11.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2006] [Revised: 11/13/2006] [Accepted: 11/14/2006] [Indexed: 12/14/2022]
Abstract
ERM (ezrin/radixin/moesin) proteins are organizers of apical actin cortical layer in general. We previously reported that the knockout of radixin resulted in Rdx(-/-) mice with displacement/loss of the canalicular transporter Mrp2, giving rise to Dubin-Johnson syndrome-like conjugated hyperbilirubinemia in the mixed genetic background (C57BL/6-129/Sv) (Kikuchi, et al. (2002) Nature Genetics 31, 320-325). However, when these mice were kept under mixed genetic background for years (late mixed backgrounds; LMB), the conjugated hyperbilirubinemia gradually became inconspicuous, while evidence of liver injury increased. We examined the effect of genetic background by backcrossing LMB Rdx(-/-) mice to C57BL/6 and 129/Sv wild type mice with the result that the Rdx(-/-) congenic mice regained hyperbilirubinemia with reduced hepatocellular damage. As revealed by immunofluorescence and western blots, the localization/expression of apical transporters, Mrp2, CD26, P-gps, and Bsep were not influenced by backcrossing, though those of a basolateral transporter, Mrp3, were strikingly increased by backcrossing.
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Affiliation(s)
- Kanehisa Fukumoto
- Department of Cell Biology, Kyoto University Faculty of Medicine, Yoshida-Konoe, Kyoto 606-8501, Japan
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43
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LaRusso NF, Shneider BL, Black D, Gores GJ, James SP, Doo E, Hoofnagle JH. Primary sclerosing cholangitis: summary of a workshop. Hepatology 2006; 44:746-64. [PMID: 16941705 DOI: 10.1002/hep.21337] [Citation(s) in RCA: 168] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Primary sclerosing cholangitis (PSC) is a rare but important liver disease that leads to cirrhosis and need for liver transplantation in a high proportion of cases. The disease occurs in approximately 1 per 100,000 population per year, usually presents in adulthood, and affects men more often than women. Typical serum biochemical results, autoantibodies and liver biopsy are suggestive but not diagnostic of PSC, the diagnosis requiring cholangiographic demonstration of stricturing and dilatation of the intra- and/or extra-hepatic bile ducts. The natural history of PSC is variable, the average survival being 12 to 17 years. The cause of PSC is still unknown. Although considered an autoimmune disease, PSC has several atypical features and a strong genetic component. The therapy of PSC is unsatisfactory. Standard doses of ursodeoxycholic acid (UDCA) lead to improvements in biochemical abnormalities but not in histology, cholangiographic appearance or survival. Several innovative therapies have been tried in PSC, but with scant evidence of benefit. For patients with high grade strictures, endoscopic dilatation is beneficial. Liver transplantation is successful for end-stage liver disease due to PSC and improves survival. PSC may recur after transplantation but is rarely progressive. The most dreaded complication of PSC is cholangiocarcinoma. Diagnosis of this highly malignant tumor is difficult, and there are no biomarkers for its early detection. Liver transplantation for cholangiocarcinoma has an exceedingly poor outcome, although transplantation with neoadjuvant chemoirradiation holds promise in selected patients. Thus, significant opportunities remain for basic and clinical research into the cause, natural history, and therapy of PSC.
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Affiliation(s)
- Nicholas F LaRusso
- Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA
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44
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Karlsen TH, Lie BA, Frey Frøslie K, Thorsby E, Broomé U, Schrumpf E, Boberg KM. Polymorphisms in the steroid and xenobiotic receptor gene influence survival in primary sclerosing cholangitis. Gastroenterology 2006; 131:781-7. [PMID: 16952547 DOI: 10.1053/j.gastro.2006.05.057] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2005] [Accepted: 05/18/2006] [Indexed: 01/06/2023]
Abstract
BACKGROUND & AIMS The steroid and xenobiotic receptor (SXR) is a ligand-dependent transcription factor that mediates protection against bile acid-induced liver injury in cholestatic animal models. Ursodeoxycholic acid and rifampicin are known ligands. We investigated whether functional polymorphisms of the SXR gene influence disease susceptibility or disease progression in patients with primary sclerosing cholangitis (PSC). METHODS Polymorphisms at 8 loci across the SXR gene were genotyped in 327 Scandinavian PSC patients and 275 healthy controls. Kaplan-Meier survival analyses and Cox regressions were performed to estimate effects from genotypes on patient survival, defined as time from diagnostic cholangiography to death or liver transplantation. RESULTS Susceptibility to PSC was not associated with any of the SXR polymorphisms studied. Median survival was significantly reduced in patients homozygous for the minor allele as compared with patients carrying at least 1 major allele of the neighboring polymorphisms rs6785049 (10.8 vs 14.0 years, respectively, P = .01), rs1054190 (3.6 vs 13.6 years, respectively, P = .004), and rs3814058 (3.5 vs 13.3 years, respectively, P = .01). The increased risk of death or liver transplantation was confirmed in univariate Cox regressions (relative risk [RR](rs6785049) = 1.7, 95% CI: 1.1-2.6; RR(rs1054190) = 3.1, 95% CI: 1.4-7.1; and RR(rs3814058) = 2.2, 95% CI: 1.2-4.2 for the 3 polymorphisms, respectively). In multiple Cox regressions including age at PSC onset, rs1054190 remained an independent risk factor. CONCLUSIONS Functional SXR gene variants appear to modify disease course in PSC. Further investigations of polymorphisms in the SXR gene may provide insight into the prognostic importance of SXR-regulated pathways in this disease, perhaps even in a therapeutic perspective.
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Affiliation(s)
- Tom H Karlsen
- Medical Department, Institute of Immunology, Rikshospitalet University Hospital, Oslo, Norway.
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45
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Zollner G, Marschall HU, Wagner M, Trauner M. Role of nuclear receptors in the adaptive response to bile acids and cholestasis: pathogenetic and therapeutic considerations. Mol Pharm 2006; 3:231-51. [PMID: 16749856 DOI: 10.1021/mp060010s] [Citation(s) in RCA: 240] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Cholestasis results in intrahepatic accumulation of cytotoxic bile acids which cause liver injury ultimately leading to biliary fibrosis and cirrhosis. Cholestatic liver damage is counteracted by a variety of intrinsic hepatoprotective mechanisms. Such defense mechanisms include repression of hepatic bile acid uptake and de novo bile acid synthesis. Furthermore, phase I and II bile acid detoxification is induced rendering bile acids more hydrophilic. In addition to "orthograde" export via canalicular export systems, these compounds are also excreted via basolateral "alternative" export systems into the systemic circulation followed by renal elimination. Passive glomerular filtration of hydrophilic bile acids, active renal tubular secretion, and repression of tubular bile acid reabsorption facilitate renal bile acid elimination during cholestasis. The underlying molecular mechanisms are mediated mainly at a transcriptional level via a complex network involving nuclear receptors and other transcription factors. So far, the farnesoid X receptor FXR, pregnane X receptor PXR, and vitamin D receptor VDR have been identified as nuclear receptors for bile acids. However, the intrinsic adaptive response to bile acids cannot fully prevent liver injury in cholestasis. Therefore, additional therapeutic strategies such as targeted activation of nuclear receptors are needed to enhance the hepatic defense against toxic bile acids.
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Affiliation(s)
- Gernot Zollner
- Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University Graz, Austria, and Karolinska University Hospital Huddinge, Stockholm, Sweden
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Briz O, Romero MR, Martinez-Becerra P, Macias RIR, Perez MJ, Jimenez F, San Martin FG, Marin JJG. OATP8/1B3-mediated cotransport of bile acids and glutathione: an export pathway for organic anions from hepatocytes? J Biol Chem 2006; 281:30326-35. [PMID: 16877380 DOI: 10.1074/jbc.m602048200] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
In cholestasis, the accumulation of organic anions in hepatocytes is reduced by transporters (multidrug resistance-associated proteins and OSTalpha-OSTbeta) able to extrude them across the basolateral membrane. Here we investigated whether organic anion-transporting polypeptides (OATPs) may contribute to this function. Xenopus laevis oocytes expressing human carboxylesterase-1 efficiently loaded cholic acid (CA) methyl ester, which was cleaved to CA and exported. Expression of OATP8/1B3 enhanced CA efflux, which was trans-activated by taurocholate but trans-inhibited by reduced (GSH) and oxidized (GSSG) glutathione. Moreover, taurocholate and estradiol 17beta-D-glucuronide, but not bicarbonate and glutamate, cis-inhibited OATP8/1B3-mediated bile acid transport, whereas glutathione cis-stimulated this process, which involved the transport of glutathione itself with a stoichiometry of 2:1 (GSH/bile acid). No cis-activation by glutathione of OATP-C/1B1 was found. Using real time quantitative reverse transcription-PCR, the absolute abundance of OATP-A/1A2, OATP-C/1B1, and OATP8/1B3 mRNA in human liver biopsies was measured. In healthy liver, expression levels of OATP-C/1B1 were approximately 5-fold those of OATP8/1B3 and >100-fold those of OATP-A/1A2. This situation was not substantially modified in several cholestatic liver diseases studied here. In conclusion, although both OATP-C/1B1 and OATP8/1B3 are highly expressed, and able to transport bile acids, their mechanisms of action are different. OATP-C/1B1 may be involved in uptake processes, whereas OATP8/1B3 may mediate the extrusion of organic anions by symporting with glutathione as a normal route of exporting metabolites produced by hepatocytes or preventing their intracellular accumulation when their vectorial traffic toward the bile is impaired.
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Affiliation(s)
- Oscar Briz
- Research Unit, University Hospital, Salamanca, Spain
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Nies AT, Keppler D. The apical conjugate efflux pump ABCC2 (MRP2). Pflugers Arch 2006; 453:643-59. [PMID: 16847695 DOI: 10.1007/s00424-006-0109-y] [Citation(s) in RCA: 261] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2006] [Accepted: 05/29/2006] [Indexed: 12/14/2022]
Abstract
ABCC2 is a member of the multidrug resistance protein subfamily localized exclusively to the apical membrane domain of polarized cells, such as hepatocytes, renal proximal tubule epithelia, and intestinal epithelia. This localization supports the function of ABCC2 in the terminal excretion and detoxification of endogenous and xenobiotic organic anions, particularly in the unidirectional efflux of substances conjugated with glutathione, glucuronate, or sulfate, as exemplified by leukotriene C(4), bilirubin glucuronosides, and some steroid sulfates. The hepatic ABCC2 pump contributes to the driving forces of bile flow. Acquired or hereditary deficiency of ABCC2, the latter known as Dubin-Johnson syndrome in humans, causes an increased concentration of bilirubin glucuronosides in blood because of their efflux from hepatocytes via the basolateral ABCC3, which compensates for the deficiency in ABCC2-mediated apical efflux. In this article we provide an overview on the molecular characteristics of ABCC2 and its expression in various tissues and species. We discuss the transcriptional and posttranscriptional regulation of ABCC2 and review approaches to the functional analysis providing information on its substrate specificity. A comprehensive list of sequence variants in the human ABCC2 gene summarizes predicted and proven functional consequences, including variants leading to Dubin-Johnson syndrome.
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Affiliation(s)
- Anne T Nies
- Division of Tumor Biochemistry, German Cancer Research Center, Heidelberg, Germany.
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48
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Geier A, Wagner M, Dietrich CG, Trauner M. Principles of hepatic organic anion transporter regulation during cholestasis, inflammation and liver regeneration. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2006; 1773:283-308. [PMID: 17291602 DOI: 10.1016/j.bbamcr.2006.04.014] [Citation(s) in RCA: 229] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2006] [Revised: 04/21/2006] [Accepted: 04/24/2006] [Indexed: 12/16/2022]
Abstract
Hepatic uptake and biliary excretion of organic anions (e.g., bile acids and bilirubin) is mediated by hepatobiliary transport systems. Defects in transporter expression and function can cause or maintain cholestasis and jaundice. Recruitment of alternative export transporters in coordination with phase I and II detoxifying pathways provides alternative pathways to counteract accumulation of potentially toxic biliary constituents in cholestasis. The genes encoding for organic anion uptake (NTCP, OATPs), canalicular export (BSEP, MRP2) and alternative basolateral export (MRP3, MRP4) in liver are regulated by a complex interacting network of hepatocyte nuclear factors (HNF1, 3, 4) and nuclear (orphan) receptors (e.g., FXR, PXR, CAR, RAR, LRH-1, SHP, GR). Bile acids, proinflammatory cytokines, hormones and drugs mediate causative and adaptive transporter changes at a transcriptional level by interacting with these nuclear factors and receptors. Unraveling the underlying regulatory mechanisms may therefore not only allow a better understanding of the molecular pathophysiology of cholestatic liver diseases but should also identify potential pharmacological strategies targeting these regulatory networks. This review is focused on general principles of transcriptional basolateral and canalicular transporter regulation in inflammation-induced cholestasis, ethinylestradiol- and pregnancy-associated cholestasis, obstructive cholestasis and liver regeneration. Moreover, the potential therapeutic role of nuclear receptor agonists for the management of liver diseases is highlighted.
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Affiliation(s)
- Andreas Geier
- Department of Internal Medicine III, Aachen University (RWTH), Aachen, Germany.
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Abstract
The nuclear farnesoid X receptor (FXR) plays a pivotal role in maintaining bile acid homeostasis by regulating key genes involved in bile acid synthesis, metabolism and transport, including CYP7A1, UGT2B4, BSEP, MDR3, MRP2, ASBT, I-BABP, NTCP and OSTalpha-OSTbeta in humans. Altered expression or malfunction of these genes has been described in patients with cholestatic liver diseases. This review examines the rationale for the use of FXR ligand therapy in various cholestatic liver disorders and includes potential concerns.
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Affiliation(s)
- Shi-Ying Cai
- Liver Center, Department of Medicine, Yale University School of Medicine, P.O. Box 208019, New Haven, CT 06520-8019, USA
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50
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Ekins S. Systems-ADME/Tox: resources and network approaches. J Pharmacol Toxicol Methods 2005; 53:38-66. [PMID: 16054403 DOI: 10.1016/j.vascn.2005.05.005] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2005] [Accepted: 05/23/2005] [Indexed: 01/11/2023]
Abstract
The increasing cost of drug development is partially due to our failure to identify undesirable compounds at an early enough stage of development. The application of higher throughput screening methods have resulted in the generation of very large datasets from cells in vitro or from in vivo experiments following the treatment with drugs or known toxins. In recent years the development of systems biology, databases and pathway software has enabled the analysis of the high-throughput data in the context of the whole cell. One of the latest technology paradigms to be applied alongside the existing in vitro and computational models for absorption, distribution, metabolism, excretion and toxicology (ADME/Tox) involves the integration of complex multidimensional datasets, termed toxicogenomics. The goal is to provide a more complete understanding of the effects a molecule might have on the entire biological system. However, due to the sheer complexity of this data it may be necessary to apply one or more different types of computational approaches that have as yet not been fully utilized in this field. The present review describes the data generated currently and introduces computational approaches as a component of ADME/Tox. These methods include network algorithms and manually curated databases of interactions that have been separately classified under systems biology methods. The integration of these disparate tools will result in systems-ADME/Tox and it is important to understand exactly what data resources and technologies are available and applicable. Examples of networks derived with important drug transporters and drug metabolizing enzymes are provided to demonstrate the network technologies.
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Affiliation(s)
- Sean Ekins
- GeneGo, 500 Renaissance Drive, Suite 106, St. Joseph, MI 49085, USA.
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