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1
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Daly AK. Genetic and Genomic Approaches to the Study of Drug-Induced Liver Injury. Liver Int 2025; 45:e16191. [PMID: 39704445 DOI: 10.1111/liv.16191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 10/29/2024] [Accepted: 11/17/2024] [Indexed: 12/21/2024]
Abstract
Idiosyncratic hepatotoxicity induced by prescribed drugs has been known since the early 20th century. Identifying risk factors, including genetic factors, that trigger this drug-induced liver injury (DILI) has been an important priority for many years, both to prevent drugs that cause liver injury being licensed and as a potential means of preventing at-risk patients being prescribed causative drugs. Improved methods for genomic analysis, particularly the development of genome-wide association studies, have facilitated the identification of genomic risk factors for DILI, but, to date, there are only two main examples, liver injury caused by amoxicillin-clavulanate (AC) and by flucloxacillin, where genetic risk factors causing the injury have been identified and replicated with understanding of the underlying mechanism. There has also been progress on identifying genetic risk factors for liver injury caused by other anti-infective agents, herbal remedies and nonsteroidal anti-inflammatory drugs. The majority of genetic risk factors identified to date are specific human leucocyte antigen (HLA) alleles and evidence that these alleles preferentially present self-peptides inappropriately to T cells in the liver has been obtained. Non-HLA genes also contribute to genetic susceptibility, both as co-factors in T-cell responses and, in the case of isoniazid-only, drug metabolism. Polygenic risk scores to predict DILI have been developed, both a simple score that predicts AC injury and complex scores that may be applied to DILI more generally and provide evidence that additional risk factors other than HLA genes exist.
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Affiliation(s)
- Ann K Daly
- Faculty of Medical Sciences, Translational & Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
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2
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Li QX, Yuan YJ, Cheng RX, Ma Y, Tan R, Wang YW, Peng Y. An AIE-active tetra-aryl imidazole-derived chemodosimeter for turn-on recognition of hydrazine and its bioimaging in living cells. Org Biomol Chem 2024. [PMID: 39011846 DOI: 10.1039/d4ob01009d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/17/2024]
Abstract
A new chemodosimeter SWJT-31 with an aggregation-induced emission (AIE) effect was designed and constructed. Upon increasing the water fraction in the solution, it exhibited typical AIE, which showed bright red fluorescence at 610 nm. SWJT-31 could sensitively and specifically recognize hydrazine by the TICT effect with an LOD of 33.8 nM, which was much lower than the standard of the USEPA. A portable test strip prepared using SWJT-31 was also developed for the visual detection of hydrazine. Eventually, it was successfully used for the detection of hydrazine in water samples and HeLa cells.
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Affiliation(s)
- Qing-Xiu Li
- School of Chemistry, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, People's Republic of China.
| | - Yan-Ju Yuan
- School of Chemistry, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, People's Republic of China.
| | - Rui-Xing Cheng
- School of Chemistry, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, People's Republic of China.
| | - Yu Ma
- School of Chemistry, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, People's Republic of China.
| | - Rui Tan
- School of Chemistry, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, People's Republic of China.
| | - Ya-Wen Wang
- School of Chemistry, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, People's Republic of China.
| | - Yu Peng
- School of Chemistry, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, People's Republic of China.
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3
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Li M, Zhang D, Yang Q, Zhao Z, Zhang C, Zhou Y, Bai Y, Chen L, Tang X, Liu C, Zhou J, Chen X, Ying B. Longitudinal metabolomics of human plasma reveal metabolic dynamics and predictive markers of antituberculosis drug-induced liver injury. Respir Res 2024; 25:254. [PMID: 38907347 PMCID: PMC11193241 DOI: 10.1186/s12931-024-02837-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Accepted: 05/04/2024] [Indexed: 06/23/2024] Open
Abstract
Tuberculosis (TB) remains the second leading cause of death from a single infectious agent and long-term medication could lead to antituberculosis drug-induced liver injury (ATB-DILI). We established a prospective longitudinal cohort of ATB-DILI with multiple timepoint blood sampling and used untargeted metabolomics to analyze the metabolic profiles of 107 plasma samples from healthy controls and newly diagnosed TB patients who either developed ATB-DILI within 2 months of anti-TB treatment (ATB-DILI subjects) or completed their treatment without any adverse drug reaction (ATB-Ctrl subjects). The untargeted metabolome revealed that 77 metabolites (of 895 total) were significantly changed with ATB-DILI progression. Among them, levels of multiple fatty acids and bile acids significantly increased over time in ATB-DILI subjects. Meanwhile, metabolites of the same class were highly correlated with each other and pathway analysis indicated both fatty acids metabolism and bile acids metabolism were up-regulated with ATB-DILI progression. The targeted metabolome further validated that 5 fatty acids had prediction capability at the early stage of the disease and 6 bile acids had a better diagnostic performance when ATB-DILI occurred. These findings provide evidence indicating that fatty acids metabolism and bile acids metabolism play a vital role during ATB-DILI progression. Our report adds a dynamic perspective better to understand the pathological process of ATB-DILI in clinical settings.
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Affiliation(s)
- Mengjiao Li
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Dan Zhang
- Department of Laboratory Medicine, State Key Laboratory of Biotherapy and Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Qingxin Yang
- Department of Laboratory Medicine, State Key Laboratory of Biotherapy and Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Zhenzhen Zhao
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Chunying Zhang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Yanbing Zhou
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Yangjuan Bai
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Lu Chen
- Department of Laboratory Medicine, State Key Laboratory of Biotherapy and Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoyan Tang
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Cuihua Liu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
| | - Juan Zhou
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China.
| | - Xuerong Chen
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China.
| | - Binwu Ying
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China.
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Surarak T, Chumnumwat S, Nosoongnoen W, Tragulpiankit P. Efficacy, safety, and pharmacokinetics of isoniazid affected by NAT2 polymorphisms in patients with tuberculosis: A systematic review. Clin Transl Sci 2024; 17:e13795. [PMID: 38629592 PMCID: PMC11022300 DOI: 10.1111/cts.13795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 03/22/2024] [Accepted: 03/30/2024] [Indexed: 04/19/2024] Open
Abstract
N-acetyltransferase 2 (NAT2) genetic polymorphisms might alter isoniazid metabolism leading to toxicity. We reviewed the impact of NAT2 genotype status on the pharmacokinetics, efficacy, and safety of isoniazid, a treatment for tuberculosis (TB). A systematic search for research articles published in Scopus, PubMed, and Embase until August 31, 2023, was conducted without filters or limits on the following search terms and Boolean operators: "isoniazid" AND "NAT2." Studies were selected if NAT2 phenotypes with pharmacokinetics or efficacy or safety of isoniazid in patients with TB were reported. Patient characteristics, NAT2 status, isoniazid pharmacokinetic parameters, early treatment failure, and the prevalence of drug-induced liver injury were extracted. If the data were given as a median, these values were standardized to the mean. Forty-one pharmacokinetics and 53 safety studies were included, but only one efficacy study was identified. The average maximum concentrations of isoniazid were expressed as supratherapeutic concentrations in adults (7.16 ± 4.85 μg/mL) and children (6.43 ± 3.87 μg/mL) in slow acetylators. The mean prevalence of drug-induced liver injury was 36.23 ± 19.84 in slow acetylators, which was significantly different from the intermediate (19.49 ± 18.20) and rapid (20.47 ± 20.68) acetylators. Subgroup analysis by continent showed that the highest mean drug-induced liver injury prevalence was in Asian slow acetylators (42.83 ± 27.61). The incidence of early treatment failure was decreased by genotype-guided isoniazid dosing in one study. Traditional weight-based dosing of isoniazid in most children and adults yielded therapeutic isoniazid levels (except for slow acetylators). Drug-induced liver injury was more commonly observed in slow acetylators. Genotype-guided dosing may prevent early treatment failure.
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Relevance of Pharmacogenomics to the Safe Use of Antimicrobials. Antibiotics (Basel) 2023; 12:antibiotics12030425. [PMID: 36978292 PMCID: PMC10044203 DOI: 10.3390/antibiotics12030425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 02/11/2023] [Accepted: 02/20/2023] [Indexed: 02/25/2023] Open
Abstract
There has been widespread implementation of pharmacogenomic testing to inform drug prescribing in medical specialties such as oncology and cardiology. Progress in using pharmacogenomic tests when prescribing antimicrobials has been more limited, though a relatively large number of pharmacogenomic studies on aspects such as idiosyncratic adverse drug reactions have now been performed for this drug class. Currently, there are recommendations in place from either National Regulatory Agencies and/or specialist Pharmacogenomics Advisory Groups concerning genotyping for specific variants in MT-RNR1 and CYP2C19 before prescribing aminoglycosides and voriconazole, respectively. Numerous additional pharmacogenomic associations have been reported concerning antimicrobial-related idiosyncratic adverse drug reactions, particularly involving specific HLA alleles, but, to date, the cost-effectiveness of genotyping prior to prescription has not been confirmed. Polygenic risk score determination has been investigated to a more limited extent but currently suffers from important limitations. Despite limited progress to date, the future widespread adoption of preemptive genotyping and genome sequencing may provide pharmacogenomic data to prescribers that can be used to inform prescribing and increase the safe use of antimicrobials.
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Crosby ME, Ciurlionis R, Brayman TG, Kondratiuk A, Nicolette JJ. Exploring the molecular and functional cellular response to hydrazine via transcriptomics and DNA repair mutant cell lines. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2022; 63:336-350. [PMID: 36176055 PMCID: PMC9828720 DOI: 10.1002/em.22508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 09/23/2022] [Indexed: 05/04/2023]
Abstract
Hydrazine is a rodent carcinogen and is classified as a probable human carcinogen by IARC. Though hydrazine is positive in both in vitro and in vivo DNA strand break (comet) assays, hydrazine was reported to be negative in an in vitro mutation Muta Mouse lung epithelial cell (FE1) test, as well as in a regulatory-compliant, in vivo Big Blue mouse mutation test. In this article, mechanistic studies explored the cellular response to hydrazine. When tested in a regulatory-compliant mouse lymphoma assay, hydrazine yielded unusual, weakly positive results. This prompted an investigation into the transcriptional response to hydrazine in FE1 cells via RNA sequencing. Amongst the changes identified was a dose-dependent increase in G2/M DNA damage checkpoint activation associated genes. Flow cytometric experiments in FE1 cells revealed that hydrazine exposure led to S-phase cell cycle arrest. Clonogenic assays in a variety of cell lines harboring key DNA repair protein deficiencies indicated that hydrazine could sensitize cells lacking homology dependent repair proteins (Brca2 and Fancg). Lastly, hprt assays with hydrazine were conducted to determine whether a lack of DNA repair could lead to mutagenicity. However, no robust, dose-dependent induction of mutations was noted. The transcriptional and cell cycle response to hydrazine, coupled with functional investigations of DNA repair-deficient cell lines support the inconsistencies noted in the genetic toxicology regulatory battery. In summary, while hydrazine may be genotoxic, transcriptional and functional processes involved in cell cycle regulation and DNA repair appear to play a nuanced role in mediating the mutagenic potential.
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Affiliation(s)
- Meredith E. Crosby
- Pre‐Clinical Safety, AbbVie Inc.North ChicagoIllinoisUnited States
- Drug Safety and PharmacometricsRegeneron Pharmaceuticals Inc.TarrytownNew YorkUnited States
| | - Rita Ciurlionis
- Pre‐Clinical Safety, AbbVie Inc.North ChicagoIllinoisUnited States
| | | | | | - John J. Nicolette
- Pre‐Clinical Safety, AbbVie Inc.North ChicagoIllinoisUnited States
- Preclinical Sciences and Translational SafetyJanssen Research and DevelopmentRaritanNew JerseyUnited States
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Lei S, Gu R, Ma X. Clinical perspectives of isoniazid-induced liver injury. LIVER RESEARCH 2021; 5:45-52. [PMID: 39959342 PMCID: PMC11791842 DOI: 10.1016/j.livres.2021.02.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 01/10/2021] [Accepted: 02/05/2021] [Indexed: 10/22/2022]
Abstract
Isoniazid (INH) is a synthetic anti-mycobacterial agent used to treat active or latent tuberculosis (TB). INH has been in clinical use for nearly 70 years and remains broadly utilized at the front line of anti-TB treatment. However, the potential for liver damage and even fulminant liver failure during INH-based TB treatment presents a major challenge for TB control programs worldwide. In this review, we discuss the hepatotoxic effects of INH and provide an overview of the mechanisms and their applications in prediction and prevention of INH hepatotoxicity in clinical practice.
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Affiliation(s)
- Saifei Lei
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA
| | - Ruizhi Gu
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA
| | - Xiaochao Ma
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA
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8
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Nicolette J, Murray J, Sonders P, Kondratiuk A, Crosby M. In vitro and in vivo mammalian mutation assays support a nonmutagenic mechanism of carcinogenicity for hydrazine. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2021; 62:4-17. [PMID: 32951273 DOI: 10.1002/em.22406] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 08/13/2020] [Accepted: 09/07/2020] [Indexed: 06/11/2023]
Abstract
Hydrazine has been described as a mutagenic, probable human carcinogen. It is mutagenic in in vitro systems such as bacterial reverse mutation (Ames) tests and some yeast systems, as well as in in vivo systems with drosophila. It was shown to cause chromosome damage both in vitro and in vivo but was negative in some well-validated mammalian mutation systems such as CHO HPRT assays. Importantly, there is only one in vivo gene mutation test reported, which was negative. Our objective was to determine if hydrazine is mutagenic in mammalian test systems. Thus, we conducted an in vitro gene mutation test in Muta™Mouse lung epithelial cells (FE1 cell assay) and a regulatory-compliant in vivo Big Blue® mouse test. Consistent with previous reports, an additional six-well Ames assay showed that hydrazine was mutagenic to bacteria. The FE1 cell assay was negative in conditions with and without metabolic activation when tested to cytotoxicity limits. In the Big Blue® mouse study, female mice received dosages of hydrazine up to 10.9 mg/kg via drinking water for 28 days. This dose is comparable to a dose used in a carcinogenicity study where female mice had significant increases in hepatocellular adenoma at 11.5 mg/kg. There were no increases in mutant frequency in liver and lung, two tissues sensitive to the carcinogenic effects of hydrazine in mice. Our research shows that hydrazine is not mutagenic in mammalian cells either in vitro or in vivo, indicating mutagenicity may not play a role in the carcinogenicity of hydrazine.
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Affiliation(s)
- John Nicolette
- Pre-Clinical Safety, AbbVie, Inc, North Chicago, Illinois, USA
| | - Joel Murray
- Pre-Clinical Safety, AbbVie, Inc, North Chicago, Illinois, USA
| | - Paul Sonders
- Pre-Clinical Safety, AbbVie, Inc, North Chicago, Illinois, USA
| | | | - Meredith Crosby
- Pre-Clinical Safety, AbbVie, Inc, North Chicago, Illinois, USA
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9
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Zhang XY, Yang YS, Wang W, Jiao QC, Zhu HL. Fluorescent sensors for the detection of hydrazine in environmental and biological systems: Recent advances and future prospects. Coord Chem Rev 2020. [DOI: 10.1016/j.ccr.2020.213367] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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10
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Arab JP, Cabrera D, Sehrawat TS, Jalan-Sakrikar N, Verma VK, Simonetto D, Cao S, Yaqoob U, Leon J, Freire M, Vargas JI, De Assuncao TM, Kwon JH, Guo Y, Kostallari E, Cai Q, Kisseleva T, Oh Y, Arrese M, Huebert RC, Shah VH. Hepatic stellate cell activation promotes alcohol-induced steatohepatitis through Igfbp3 and SerpinA12. J Hepatol 2020; 73:149-160. [PMID: 32087348 PMCID: PMC7305991 DOI: 10.1016/j.jhep.2020.02.005] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 01/23/2020] [Accepted: 02/01/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Steatohepatitis drives fibrogenesis in alcohol-related liver disease. Recent studies have suggested that hepatic stellate cells (HSCs) may regulate the parenchymal cell injury and inflammation that precedes liver fibrosis, although the mechanism remains incompletely defined. Neuropilin-1 (NRP-1) and synectin are membrane proteins implicated in HSC activation. In this study, we disrupted NRP-1 and synectin as models to evaluate the role of HSC activation on the development of steatohepatitis in response to alcohol feeding in mice. METHODS Mice with HSC-selective deletion of NRP (ColCre/Nrp1loxP) or synectin (ColCre/synectinloxP) vs. paired Nrp1loxP or synectinloxP mice were fed a control diet or the chronic/binge alcohol feeding model. Several markers of steatosis and inflammation were evaluated. RESULTS ColCre/Nrp1loxP mice showed less fibrosis, as expected, but also less inflammation and steatosis, with lower hepatic triglyceride content. Similar results were observed in the synectin model. Hepatocytes treated with supernatant of HSCs from ColCre/Nrp1loxP mice compared to supernatant from Nrp1loxP mice were protected against ethanol-induced lipid droplet formation. An adipokine and inflammatory protein array from the supernatant of HSCs with NRP-1 knockdown showed a significant reduction in Igfbp3 (a major insulin-like growth factor-binding protein with multiple metabolic functions) and an increase in SerpinA12 (a serine-protease inhibitor) secretion compared to wild-type HSCs. Recombinant Igfbp3 induced lipid droplets, triglyceride accumulation, and lipogenic genes in hepatocytes in vitro, while SerpinA12 was protective against ethanol-induced steatosis. Finally, Igfbp3 was increased, and SerpinA12 was decreased in serum and liver tissue from patients with alcoholic hepatitis. CONCLUSION Selective deletion of NRP-1 from HSCs attenuates alcohol-induced steatohepatitis through regulation of Igfbp3 and SerpinA12 signaling. LAY SUMMARY Hepatic stellate cells are known for their role in fibrosis (scarring of the liver). In this study, we describe their role in the modulation of fat deposition and inflammation in the liver, which occurs secondary to alcohol damage.
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Affiliation(s)
- Juan P Arab
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA; Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Daniel Cabrera
- Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile; Departamento de Ciencias Químicas y Biológicas, Universidad Bernardo O Higgins, Santiago, Chile
| | - Tejasav S Sehrawat
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | | | - Vikas K Verma
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Douglas Simonetto
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Sheng Cao
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Usman Yaqoob
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Jonathan Leon
- Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Mariela Freire
- Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Jose I Vargas
- Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | | | - Jung H Kwon
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Yi Guo
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Enis Kostallari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Qing Cai
- Department of Pathology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA
| | - Tatiana Kisseleva
- Department of Surgery, University of California-San Diego, San Diego, CA, USA
| | - Youngman Oh
- Department of Pathology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA
| | - Marco Arrese
- Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Robert C Huebert
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
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Brewer CT, Yang L, Edwards A, Lu Y, Low J, Wu J, Lee RE, Chen T. The Isoniazid Metabolites Hydrazine and Pyridoxal Isonicotinoyl Hydrazone Modulate Heme Biosynthesis. Toxicol Sci 2019; 168:209-224. [PMID: 30517741 PMCID: PMC6390808 DOI: 10.1093/toxsci/kfy294] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
In a mouse model, rifampicin and isoniazid combination treatment results in cholestatic liver injury that is associated with an increase in protoporphyrin IX, the penultimate heme precursor. Both ferrochelatase (FECH/Fech) and aminolevulinic acid synthase 1 (ALAS1/Alas1) are crucial enzymes in regulating heme biosynthesis. Isoniazid has recently been reported to upregulate Alas1 but downregulate Fech protein levels in mice; however, the mechanism by which isoniazid mediates disruption of heme synthesis has been unclear. Two metabolites of isoniazid, pyridoxal isonicotinoyl hydrazone (PIH, the isoniazid-vitamin B6 conjugate) and hydrazine, have been detected in the urine of humans treated with isoniazid. Here we show that, in primary human hepatocytes and the human hepatocellular carcinoma cell line HepG2/C3A, (1) isoniazid treatment increases Alas1 protein levels but decreases Fech levels; (2) hydrazine treatment upregulates Alas1 protein and Alas1 mRNA levels; (3) PIH treatment decreases Fech protein levels, but not Fech mRNA levels; and (4) PIH is detected after isoniazid treatment, with levels increasing further when exogenous vitamin B6 analogs are coadministered. In addition, the PIH-mediated downregulation of human FECH is associated with iron chelation. Together, these data demonstrate that hydrazine upregulates ALAS1, whereas PIH downregulates FECH, suggesting that the metabolites of isoniazid mediate its disruption of heme biosynthesis by contributing to protoporphyrin IX accumulation.
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Affiliation(s)
- Christopher Trent Brewer
- Department of Chemical Biology and Therapeutics, St Jude Children’s Research Hospital, Memphis, Tennessee 38105
- Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, Tennessee 38163
| | - Lei Yang
- Department of Chemical Biology and Therapeutics, St Jude Children’s Research Hospital, Memphis, Tennessee 38105
| | - Anne Edwards
- Department of Chemical Biology and Therapeutics, St Jude Children’s Research Hospital, Memphis, Tennessee 38105
| | - Yan Lu
- Department of Chemical Biology and Therapeutics, St Jude Children’s Research Hospital, Memphis, Tennessee 38105
| | - Jonathan Low
- Department of Chemical Biology and Therapeutics, St Jude Children’s Research Hospital, Memphis, Tennessee 38105
| | - Jing Wu
- Department of Chemical Biology and Therapeutics, St Jude Children’s Research Hospital, Memphis, Tennessee 38105
| | - Richard E Lee
- Department of Chemical Biology and Therapeutics, St Jude Children’s Research Hospital, Memphis, Tennessee 38105
| | - Taosheng Chen
- Department of Chemical Biology and Therapeutics, St Jude Children’s Research Hospital, Memphis, Tennessee 38105
- Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, Tennessee 38163
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12
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Carpéné C, Boulet N, Chaplin A, Mercader J. Past, Present and Future Anti-Obesity Effects of Flavin-Containing and/or Copper-Containing Amine Oxidase Inhibitors. MEDICINES (BASEL, SWITZERLAND) 2019; 6:E9. [PMID: 30650583 PMCID: PMC6473341 DOI: 10.3390/medicines6010009] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 01/10/2019] [Accepted: 01/11/2019] [Indexed: 12/12/2022]
Abstract
Background: Two classes of amine oxidases are found in mammals: those with a flavin adenine dinucleotide as a cofactor, such as monoamine oxidases (MAO) and lysine-specific demethylases (LSD), and those with copper as a cofactor, including copper-containing amine oxidases (AOC) and lysyl oxidases (LOX). All are expressed in adipose tissue, including a semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1) strongly present on the adipocyte surface. Methods: Previously, irreversible MAO inhibitors have been reported to limit food intake and/or fat extension in rodents; however, their use for the treatment of depressed patients has not revealed a clear anti-obesity action. Semicarbazide and other molecules inhibiting SSAO/VAP-1 also reduce adiposity in obese rodents. Results: Recently, a LOX inhibitor and a subtype-selective MAO inhibitor have been shown to limit fattening in high-fat diet-fed rats. Phenelzine, which inhibits MAO and AOC, limits adipogenesis in cultured preadipocytes and impairs lipogenesis in mature adipocytes. When tested in rats or mice, phenelzine reduces food intake and/or fat accumulation without cardiac adverse effects. Novel amine oxidase inhibitors have been recently characterized in a quest for promising anti-inflammatory or anti-cancer approaches; however, their capacity to mitigate obesity has not been studied so far. Conclusions: The present review of the diverse effects of amine oxidase inhibitors impairing adipocyte differentiation or limiting excessive fat accumulation indicates that further studies are needed to reveal their potential anti-obesity properties.
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Affiliation(s)
- Christian Carpéné
- Institute of Metabolic and Cardiovascular Diseases, INSERM, UMR1048, Team 1, 31432 Toulouse, France.
- I2MC, University of Toulouse, UMR1048, Paul Sabatier University, 31432 Toulouse Cedex 4, France.
| | - Nathalie Boulet
- Institute of Metabolic and Cardiovascular Diseases, INSERM, UMR1048, Team 1, 31432 Toulouse, France.
- I2MC, University of Toulouse, UMR1048, Paul Sabatier University, 31432 Toulouse Cedex 4, France.
| | - Alice Chaplin
- Cardiovascular Research Institute, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
| | - Josep Mercader
- Department of Fundamental Biology and Health Sciences, University of the Balearic Islands, 07122 Palma, Spain.
- Balearic Islands Health Research Institute (IdISBa), 07122 Palma, Spain.
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13
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John P, Kale PP. Prominence of Oxidative Stress in the Management of Anti-tuberculosis Drugs Related Hepatotoxicity. Drug Metab Lett 2019; 13:95-101. [PMID: 31333143 DOI: 10.2174/1872312813666190716155930] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 05/08/2019] [Accepted: 06/03/2019] [Indexed: 06/10/2023]
Abstract
Advanced medical services and treatments are available for treating Tuberculosis. Related prevalence has increased in recent times. Unfortunately, the continuous consumption of related drugs is also known for inducing hepatotoxicity which is a critical condition and cannot be overlooked. The present review article has focused on the pathways causing these toxicities and also the role of enzyme CYP2E1, hepatic glutathione, Nrf2-ARE signaling pathway, and Membrane Permeability Transition as possible targets which may help in preventing the hepatotoxicity induced by the drugs used in the treatment of tuberculosis.
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Affiliation(s)
- Preena John
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle, Mumbai-400056, Maharashtra, India
| | - Pravin P Kale
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle, Mumbai-400056, Maharashtra, India
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14
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Yu JC, Hsu FC, Chiu YF. Assessment of fenofibrate-methylation interactions on triglycerides using longitudinal family data. BMC Proc 2018; 12:48. [PMID: 30263049 PMCID: PMC6156834 DOI: 10.1186/s12919-018-0132-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Background Triglyceride (TG) concentrations decrease in response to fenofibrate treatment, and also are associated with DNA methylation. But how interactions between fenofibrate response and DNA methylation affect TGs remains unclear. Methods In the present study, we identified and compared differential methylation sites associated with TG concentrations in individuals before and after fenofibrate treatment. We then estimated interactions between fenofibrate treatment and methylation to identify differential methylation effects associated with fenofibrate treatment on TG concentrations using the entire longitudinal family sample. To account for within-family and within-individual corrections, the generalized estimating equations approach was used to estimate main and interaction effects between methylation sites and fenofibrate treatment, adjusting for potential confounders. Analyses were also performed with and without adjusting for high-density lipoprotein (HDL) concentrations. Results Prior to fenofibrate treatment, 23 cytosine-phosphate-guanine (CpG) sites were significantly associated with TG concentrations, while only 13 CpG sites were identified posttreatment, adjusting for HDL. Without adjusting for HDL, pretreatment, 20 CpG sites were significantly associated with TG concentrations, while only 12 CpG sites were identified posttreatment. Among these sites, only one differential site (cg19003390 in the CPT1A gene) overlapped from pre- and posttreatment measurements regardless of HDL adjustment. Furthermore, 11 methylation sites showed substantial interaction effects (p < 1.43 × 10−7with Bonferroni correction) with or without HDL adjustment when using the whole longitudinal data. Conclusions Our analyses suggest that DNA methylation likely modified the effect of fenofibrate on TG concentrations. Differential fenofibrate-associated methylation sites on TGs differed with and without adjusting for HDL concentrations, suggesting that these HDLs and TGs might share some common epigenetic processes.
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Affiliation(s)
- Jih-Chang Yu
- 1Institute of Population Health Sciences, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli, 35053 Taiwan
| | - Fang-Chi Hsu
- 2Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Medical City Boulevard, Winston-Salem, NC 27157 USA
| | - Yen-Feng Chiu
- 1Institute of Population Health Sciences, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli, 35053 Taiwan
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15
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Li F, Wang P, Liu K, Tarrago MG, Lu J, Chini EN, Ma X. A High Dose of Isoniazid Disturbs Endobiotic Homeostasis in Mouse Liver. Drug Metab Dispos 2016; 44:1742-1751. [PMID: 27531952 PMCID: PMC5074471 DOI: 10.1124/dmd.116.070920] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2016] [Accepted: 08/15/2016] [Indexed: 11/22/2022] Open
Abstract
Overdose of isoniazid (INH), an antituberculosis drug, can be life-threatening because of neurotoxicity. In clinical practice for management of INH overdose and acute toxicity, the potential of INH-induced hepatotoxicity is also considered. However, the biochemical basis of acute INH toxicity in the liver remains elusive. In the current study, we used an untargeted metabolomic approach to explore the acute effects of INH on endobiotic homeostasis in mouse liver. We found that overdose of INH resulted in accumulation of oleoyl-l-carnitine and linoleoyl-l-carnitine in the liver, indicating mitochondrial dysfunction. We also revealed the interactions between INH and fatty acyl-CoAs by identifying INH-fatty acid amides. In addition, we found that overdose of INH led to the accumulation of heme and oxidized NAD in the liver. We also identified an INH and NAD adduct in the liver. In this adduct, the nicotinamide moiety in NAD was replaced by INH. Furthermore, we illustrated that overdose of INH depleted vitamin B6 in the liver and blocked vitamin B6-dependent cystathionine degradation. These data suggest that INH interacts with multiple biochemical pathways in the liver during acute poisoning caused by INH overdose.
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Affiliation(s)
- Feng Li
- Department of Molecular and Cellular Biology, Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas (F.L.); Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (P.W., K.L., J.L., X.M.), Laboratory of Signal Transduction, Department of Anesthesiology and Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, Minnesota (M.G.T., E.N.C.)
| | - Pengcheng Wang
- Department of Molecular and Cellular Biology, Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas (F.L.); Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (P.W., K.L., J.L., X.M.), Laboratory of Signal Transduction, Department of Anesthesiology and Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, Minnesota (M.G.T., E.N.C.)
| | - Ke Liu
- Department of Molecular and Cellular Biology, Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas (F.L.); Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (P.W., K.L., J.L., X.M.), Laboratory of Signal Transduction, Department of Anesthesiology and Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, Minnesota (M.G.T., E.N.C.)
| | - Mariana G Tarrago
- Department of Molecular and Cellular Biology, Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas (F.L.); Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (P.W., K.L., J.L., X.M.), Laboratory of Signal Transduction, Department of Anesthesiology and Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, Minnesota (M.G.T., E.N.C.)
| | - Jie Lu
- Department of Molecular and Cellular Biology, Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas (F.L.); Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (P.W., K.L., J.L., X.M.), Laboratory of Signal Transduction, Department of Anesthesiology and Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, Minnesota (M.G.T., E.N.C.)
| | - Eduardo N Chini
- Department of Molecular and Cellular Biology, Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas (F.L.); Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (P.W., K.L., J.L., X.M.), Laboratory of Signal Transduction, Department of Anesthesiology and Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, Minnesota (M.G.T., E.N.C.)
| | - Xiaochao Ma
- Department of Molecular and Cellular Biology, Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas (F.L.); Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (P.W., K.L., J.L., X.M.), Laboratory of Signal Transduction, Department of Anesthesiology and Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, Minnesota (M.G.T., E.N.C.)
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16
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Isoniazid metabolism and hepatotoxicity. Acta Pharm Sin B 2016; 6:384-392. [PMID: 27709007 PMCID: PMC5045547 DOI: 10.1016/j.apsb.2016.07.014] [Citation(s) in RCA: 145] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Revised: 06/09/2016] [Accepted: 06/27/2016] [Indexed: 12/17/2022] Open
Abstract
Isoniazid (INH) is highly effective for the management of tuberculosis. However, it can cause liver injury and even liver failure. INH metabolism has been thought to be associated with INH-induced liver injury. This review summarized the metabolic pathways of INH and discussed their associations with INH-induced liver injury.
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Key Words
- ALP, alkaline phosphatase
- ALT, alanine aminotransferase
- AcHz, acetylhydrazine
- AcINH, acetylisoniazid
- Amidase
- Anti-tuberculosis
- DiAcHz, diacetylhydrazine
- GSH, glutathione
- GST, glutathione S-transferase
- Hepatotoxicity
- Hz, hydrazine
- INA, isonicotinic acid
- INH, isoniazid
- Isoniazid
- MPO, myeloperoxidase
- Metabolism
- N-Acetyltransferase 2
- NAD+, nicotinamide adenine dinucleotide
- NAT, N-acetyltransferase
- P450, cytochrome P450
- R.M., reactive metabolite
- TB, tuberculosis
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17
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Hassan HM, Guo HL, Yousef BA, Luyong Z, Zhenzhou J. Hepatotoxicity mechanisms of isoniazid: A mini-review. J Appl Toxicol 2015; 35:1427-32. [DOI: 10.1002/jat.3175] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Accepted: 04/17/2015] [Indexed: 12/25/2022]
Affiliation(s)
- Hozeifa M. Hassan
- Jiangsu Key Laboratory of Drug Screening; China Pharmaceutical University; Nanjing China
- Department of Pharmacology, Faculty of Pharmacy; University of Gezira; Wad-Medani Sudan
| | - Hong-li Guo
- Jiangsu Key Laboratory of Drug Screening; China Pharmaceutical University; Nanjing China
| | - Bashir A. Yousef
- Jiangsu Key Laboratory of Drug Screening; China Pharmaceutical University; Nanjing China
- Department of Pharmacology, Faculty of Pharmacy; University of Khartoum; Khartoum Sudan
| | - Zhang Luyong
- Jiangsu Key Laboratory of Drug Screening; China Pharmaceutical University; Nanjing China
- Jiangsu Center for Pharmacodynamics Research and Evaluation; China Pharmaceutical University; Nanjing China
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research; China Pharmaceutical University; Nanjing China
| | - Jiang Zhenzhou
- Jiangsu Key Laboratory of Drug Screening; China Pharmaceutical University; Nanjing China
- Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University); Ministry of Education; Nanjing China
- State Key Laboratory of Natural Medicines; China Pharmaceutical University; Nanjing China
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18
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Cui Y, Liu H, Ze Y, Zengli Z, Hu Y, Cheng Z, Cheng J, Hu R, Gao G, Wang L, Tang M, Hong F. Gene expression in liver injury caused by long-term exposure to titanium dioxide nanoparticles in mice. Toxicol Sci 2012; 128:171-85. [PMID: 22539623 DOI: 10.1093/toxsci/kfs153] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Although liver toxicity induced by titanium dioxide nanoparticles (TiO(2) NPs) has been demonstrated, very little is known about the molecular mechanisms of multiple genes working together underlying this type of liver injury in mice. In this study, we used the whole-genome microarray analysis technique to determine the gene expression profile in the livers of mice exposed to 10 mg/kg body weight TiO(2) NPs for 90 days. The findings showed that long-term exposure to TiO(2) NPs resulted in obvious titanium accumulation in the liver and TiO(2) NP aggregation in hepatocyte nuclei, an inflammatory response, hepatocyte apoptosis, and liver dysfunction. Furthermore, microarray data showed striking changes in the expression of 785 genes related to the immune/inflammatory response, apoptosis, oxidative stress, the metabolic process, response to stress, cell cycle, ion transport, signal transduction, cell proliferation, cytoskeleton, and cell differentiation in TiO(2) NP-exposed livers. In particular, a significant reduction in complement factor D (Cfd) expression following long-term exposure to TiO(2) NPs resulted in autoimmune and inflammatory disease states in mice. Therefore, Cfd may be a potential biomarker of liver toxicity caused by TiO(2) NPs exposure.
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Affiliation(s)
- Yaling Cui
- Medical College, Soochow University, Suzhou 215123, People's Republic of China
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19
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Singh M, Sasi P, Gupta VH, Rai G, Amarapurkar DN, Wangikar PP. Protective effect of curcumin, silymarin and N-acetylcysteine on antitubercular drug-induced hepatotoxicity assessed in an in vitro model. Hum Exp Toxicol 2012; 31:788-97. [PMID: 22318308 DOI: 10.1177/0960327111433901] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Tuberculosis (TB) is highly endemic in India. The first-line anti-TB therapy (ATT) involving isoniazid (INH), rifampicin and pyrazinamide causes hepatotoxicity in approximately 11.5% of Indian patients. Studies have shown that ATT-induced hepatotoxicity is primarily due to oxidative stress caused by the drugs and metabolites. Herbal drugs with antioxidative properties have been tested in animal studies and clinical trials for the management of hepatotoxicity. The objective of this study was to investigate the role of curcumin (CUR), silymarin (SILY) and N-acetylcysteine (N-ACET) on hepatotoxicity by ATT drugs using an in vitro model of human hepatocellular carcinoma cell line (HepG2). HepG2 cells were treated with ATT drugs alone or along with CUR, SILY or N-ACET for a 48-h duration. The cells were monitored for viability, morphology, respiring mitochondria and cell cycle. Our results suggest that the presence of hepatoprotective drugs during treatment of HepG2 cells with ATT drugs lowers the hepatotoxic effect of the latter. This is observed in terms of (a) increased cell viability, (b) healthy-looking cell morphology as revealed by phase contrast microscopy, (c) active respiring cells as observed with confocal microscopy upon staining with a mitochondrial membrane-specific dye, MitoTracker(®) Red, and reduction in the sub-G(1) peak in cell cycle analysis by flow cytometry. Our results suggest that these hepatoprotective drugs need to be further explored as potential adjuvant therapy along with ATT drugs.
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Affiliation(s)
- M Singh
- Department of Chemical Engineering, Indian Institute of Technology Bombay, Powai, Mumbai, Maharashtra, India
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20
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Khan FY, Rasoul F. Rifampicin-isoniazid induced fatal fulminant hepatitis during treatment of latent tuberculosis: A case report and literature review. Indian J Crit Care Med 2011; 14:97-100. [PMID: 20859496 PMCID: PMC2936741 DOI: 10.4103/0972-5229.68226] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
A 42-year-old Indian man received 450 mg rifampicin (RIF) and 150 mg isoniazid (INH) daily after being diagnosed of a latent tuberculosis infection. Baseline serum aminotransferase and total bilirubin levels were within normal limits. On day 31 of treatment, the patient experienced epigastric discomfort and general malaise and one week later he developed nausea and episodic vomiting. The patient missed his first scheduled clinic appointment and he continued taking RIF-INH despite his symptoms. He visited the tuberculosis clinic on day 47 of treatment where he was found to be jaundiced and his liver enzymes were elevated. RIF-INH was stopped and the patient was admitted to our hospital as a case of RIF-INH induced hepatitis. On the 7th day of hospitalization, the patient developed consciousness disturbance with flapping tremor and high ammonia level. The patient was diagnosed with fulminant hepatic failure and transferred immediately to the medical intensive care unit, where he died 4 days later.
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Affiliation(s)
- Fahmi Yousef Khan
- Hamad General Hospital, Department of Medicine, P.O.Box : 3050, Doha - Qatar
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21
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Sampath H, Batra AK, Vartanian V, Carmical JR, Prusak D, King IB, Lowell B, Earley LF, Wood TG, Marks DL, McCullough AK, R Stephen L. Variable penetrance of metabolic phenotypes and development of high-fat diet-induced adiposity in NEIL1-deficient mice. Am J Physiol Endocrinol Metab 2011; 300:E724-34. [PMID: 21285402 PMCID: PMC3074946 DOI: 10.1152/ajpendo.00387.2010] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Exposure to chronic and acute oxidative stress is correlated with many human diseases, including, but not limited to, cancer, heart disease, diabetes, and obesity. In addition to cellular lipids and proteins, cellular oxidative stress can result in damage to DNA bases, especially in mitochondrial DNA. We previously described the development of spontaneous late-onset obesity, hepatic steatosis, hyperinsulinemia, and hyperleptinemia in mice that are deficient in the DNA glycosylase nei-like 1 (NEIL1), which initiates base excision repair of several oxidatively damaged bases. In the current study, we report that exposure to a chronic oxidative stress in the form of a high-fat diet greatly accelerates the development of obesity in neil1(-/-) mice. Following a 5-wk high-fat diet challenge, neil1(-/-) mice gained significantly more body weight than neil1(+/+) littermates and had increased body fat accumulation and moderate to severe hepatic steatosis. Analysis of oxygen consumption by indirect calorimetry indicated a modest reduction in total oxygen consumption in neil1(-/-) mice that was abolished upon correction for lean body mass. Additionally, hepatic expression of several inflammatory genes was significantly upregulated in neil1(-/-) mice following high-fat diet challenge compared with chow-fed or neil1(+/+) counterparts. A long-term high-fat diet also induced glucose intolerance as well as a significant reduction in mitochondrial DNA and protein content in neil1(-/-) mice. Collectively, these data indicate that NEIL1 deficiency results in an increased susceptibility to obesity and related complications potentially by lowering the threshold for tolerance of cellular oxidative stress in neil1(-/-) mice.
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Affiliation(s)
- Harini Sampath
- Center for Research on Occupational and Environmental Toxicology, Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, USA
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22
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Ge F, Lobdell H, Zhou S, Hu C, Berk PD. Digital analysis of hepatic sections in mice accurately quantitates triglycerides and selected properties of lipid droplets. Exp Biol Med (Maywood) 2010; 235:1282-6. [PMID: 20975077 DOI: 10.1258/ebm.2010.010095] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
We describe a method for the histologic evaluation of lipid accumulation in the livers of various mouse models of hepatic steatosis based on quantitative digital analysis of Oil Red O (ORO) accumulation in fresh-frozen hepatic sections. The process involves two principal steps: identification and digital photographic imaging of areas appropriate for analysis, followed by digital determination of the fraction of the identified area (Area Fraction) exhibiting ORO staining. The Area Fraction, designated the Digital Steatosis Score, is a valuable aspect of the histologic assessment of the liver, especially in various forms of alcoholic and non-alcoholic liver diseases. The method is rapid, requiring ∼3 min per specimen, and highly reproducible, avoiding the inevitably subjective, semi-quantitative evaluation of lipid content inherent in visual steatosis scoring systems. In normal mice and in six different mouse models of fatty liver, the Area Fraction was highly correlated with hepatic triglyceride content (P < 0.01). The coefficient of variation of repeated determinations of the Area Fraction by two different observers was ±6.4%. If made available in clinical settings, rapid, accurate quantitation of liver triglycerides by this method could be very useful in specific conditions such as assessment of donor livers for transplantation.
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Affiliation(s)
- Fengxia Ge
- The Department of Medicine, Divisions of Digestive & Liver Disease, Columbia University Medical Center, Columbia University College of Physicians & Surgeons, New York, NY 10032, USA
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23
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Determination of the key innate genes related to individual variation in carbon tetrachloride-induced hepatotoxicity using a pre-biopsy procedure. Toxicol Appl Pharmacol 2009; 239:55-63. [DOI: 10.1016/j.taap.2009.05.018] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2009] [Revised: 04/21/2009] [Accepted: 05/15/2009] [Indexed: 01/17/2023]
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24
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Ballester PJ, Westwood I, Laurieri N, Sim E, Richards WG. Prospective virtual screening with Ultrafast Shape Recognition: the identification of novel inhibitors of arylamine N-acetyltransferases. J R Soc Interface 2009; 7:335-42. [PMID: 19586957 DOI: 10.1098/rsif.2009.0170] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
There is currently a shortage of chemical molecules that can be used as bioactive probes to study molecular targets and potentially as starting points for drug discovery. One inexpensive way to address this problem is to use computational methods to screen a comprehensive database of small molecules to discover novel structures that could lead to alternative and better bioactive probes. Despite that pleasing logic the results have been somewhat mixed. Here we describe a virtual screening technique based on ligand-receptor shape complementarity, Ultrafast Shape Recognition (USR). USR is specifically applied to identify novel inhibitors of arylamine N-acetyltransferases by computationally screening almost 700 million molecular conformers in a time- and resource-efficient manner. A small number of the predicted active compounds were purchased and tested obtaining a confirmed hit rate of 40 per cent which is an outstanding result for a prospective virtual screening.
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Affiliation(s)
- Pedro J Ballester
- Physical & Theoretical Chemistry Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QZ, UK.
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25
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Chen C, Krausz KW, Shah YM, Idle JR, Gonzalez FJ. Serum metabolomics reveals irreversible inhibition of fatty acid beta-oxidation through the suppression of PPARalpha activation as a contributing mechanism of acetaminophen-induced hepatotoxicity. Chem Res Toxicol 2009; 22:699-707. [PMID: 19256530 DOI: 10.1021/tx800464q] [Citation(s) in RCA: 126] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Metabolic bioactivation, glutathione depletion, and covalent binding are the early hallmark events after acetaminophen (APAP) overdose. However, the subsequent metabolic consequences contributing to APAP-induced hepatic necrosis and apoptosis have not been fully elucidated. In this study, serum metabolomes of control and APAP-treated wild-type and Cyp2e1-null mice were examined by liquid chromatography-mass spectrometry (LC-MS) and multivariate data analysis. A dose-response study showed that the accumulation of long-chain acylcarnitines in serum contributes to the separation of wild-type mice undergoing APAP-induced hepatotoxicity from other mouse groups in a multivariate model. This observation, in conjunction with the increase of triglycerides and free fatty acids in the serum of APAP-treated wild-type mice, suggested that APAP treatment can disrupt fatty acid beta-oxidation. A time-course study further indicated that both wild-type and Cyp2e1-null mice had their serum acylcarnitine levels markedly elevated within the early hours of APAP treatment. While remaining high in wild-type mice, serum acylcarnitine levels gradually returned to normal in Cyp2e1-null mice at the end of the 24 h treatment. Distinct from serum aminotransferase activity and hepatic glutathione levels, the pattern of serum acylcarnitine accumulation suggested that acylcarnitines can function as complementary biomarkers for monitoring the APAP-induced hepatotoxicity. An essential role for peroxisome proliferator-activated receptor alpha (PPARalpha) in the regulation of serum acylcarnitine levels was established by comparing the metabolomic responses of wild-type and Ppara-null mice to a fasting challenge. The upregulation of PPARalpha activity following APAP treatment was transient in wild-type mice but was much more prolonged in Cyp2e1-null mice. Overall, serum metabolomics of APAP-induced hepatotoxicity revealed that the CYP2E1-mediated metabolic activation and oxidative stress following APAP treatment can cause irreversible inhibition of fatty acid oxidation, potentially through suppression of PPARalpha-regulated pathways.
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Affiliation(s)
- Chi Chen
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
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26
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Merrick BA, Witzmann FA. The role of toxicoproteomics in assessing organ specific toxicity. EXS 2009; 99:367-400. [PMID: 19157068 DOI: 10.1007/978-3-7643-8336-7_13] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Aims of this chapter on the role of toxicoproteomics in assessing organ-specific toxicity are to define the field of toxicoproteomics, describe its development among global technologies, and show potential uses in experimental toxicological research, preclinical testing and mechanistic biological research. Disciplines within proteomics deployed in preclinical research are described as Tier I analysis, involving global protein mapping and protein profiling for differential expression, and Tier II proteomic analysis, including global methods for description of function, structure, interactions and post-translational modification of proteins. Proteomic platforms used in toxicoproteomics research are briefly reviewed. Preclinical toxicoproteomic studies with model liver and kidney toxicants are critically assessed for their contributions toward understanding pathophysiology and in biomarker discovery. Toxicoproteomics research conducted in other organs and tissues are briefly discussed as well. The final section suggests several key developments involving new approaches and research focus areas for the field of toxicoproteomics as a new tool for toxicological pathology.
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Affiliation(s)
- B Alex Merrick
- Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, Durham, NC 27709, USA.
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27
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Russell AJ, Westwood IM, Crawford MH, Robinson J, Kawamura A, Redfield C, Laurieri N, Lowe ED, Davies SG, Sim E. Selective small molecule inhibitors of the potential breast cancer marker, human arylamine N-acetyltransferase 1, and its murine homologue, mouse arylamine N-acetyltransferase 2. Bioorg Med Chem 2009; 17:905-18. [DOI: 10.1016/j.bmc.2008.11.032] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2008] [Revised: 11/06/2008] [Accepted: 11/12/2008] [Indexed: 10/21/2022]
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28
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Adhvaryu MR, Reddy NM, Vakharia BC. Prevention of hepatotoxicity due to anti tuberculosis treatment: A novel integrative approach. World J Gastroenterol 2008; 14:4753-62. [PMID: 18720535 PMCID: PMC2739336 DOI: 10.3748/wjg.14.4753] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the ability of Curcuma longa (CL) and Tinospora cordifolia (TC) formulation to prevent anti-tuberculosis (TB) treatment (ATT) induced hepatotoxicity.
METHODS: Patients with active TB diagnosis were randomized to a drug control group and a trial group on drugs plus an herbal formulation. Isoniazid, rifampicin, pyrazinamide and ethambutol for first 2 mo followed by continuation phase therapy excluding Pyrazinamide for 4 mo comprised the anti-tuberculous treatment. Curcumin enriched (25%) CL and a hydro-ethanolic extract enriched (50%) TC 1 g each divided in two doses comprised the herbal adjuvant. Hemogram, bilirubin and liver enzymes were tested initially and monthly till the end of study to evaluate the result.
RESULTS: Incidence and severity of hepatotoxicity was significantly lower in trial group (incidence: 27/192 vs 2/316, P < 0.0001). Mean aspartate transaminase (AST) (195.93 ± 108.74 vs 85 ± 4.24, P < 0.0001), alanine transaminase (ALT) (75.74 ± 26.54 vs 41 ± 1.41, P < 0.0001) and serum bilirubin (5.4 ± 3.38 vs 1.5 ± 0.42, P < 0.0001). A lesser sputum positivity ratio at the end of 4 wk (10/67 vs 4/137, P = 0.0068) and decreased incidence of poorly resolved parenchymal lesion at the end of the treatment (9/152 vs 2/278, P = 0.0037) was observed. Improved patient compliance was indicated by nil drop-out in trial vs 10/192 in control group (P < 0.0001).
CONCLUSION: The herbal formulation prevented hepatotoxicity significantly and improved the disease outcome as well as patient compliance without any toxicity or side effects.
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Wakefield L, Cornish V, Long H, Kawamura A, Zhang X, Hein DW, Sim E. Mouse arylamine N-acetyltransferase 2 (Nat2) expression during embryogenesis: a potential marker for the developing neuroendocrine system. Biomarkers 2008; 13:106-18. [PMID: 17896208 PMCID: PMC2430772 DOI: 10.1080/13547500701673529] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Arylamine N-acetyltransferase (NAT) genes in humans and in rodents encode polymorphic drug metabolizing enzymes. Human NAT1 (and the murine equivalent mouse Nat2) is found early in embryonic development and is likely to have an endogenous role. We report the detailed expression of the murine gene (Nat2) and encoded protein in mouse embryos, using a transgenic mouse model bearing a lacZ transgene inserted into the coding region of mouse Nat2. In mouse embryos, the transgene was expressed in sensory epithelia, epithelial placodes giving rise to visceral sensory neurons, the developing pituitary gland, sympathetic chain and urogenital ridge. In Nat2+/+ mice, the presence and activity of Nat2 protein was detected in these tissues and their adult counterparts. Altered expression of the human orthologue in breast tumours, in which there is endocrine signalling, suggests that human NAT1 should be considered as a potential biomarker for neuroendocrine tissues and tumours.
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Affiliation(s)
- Larissa Wakefield
- Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK
| | - Valerie Cornish
- Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK
| | - Hilary Long
- Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK
| | - Akane Kawamura
- Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK
| | - Xiaoyan Zhang
- Department of Pharmacology and Toxicology and James Graham Brown Center, University of Louisville School of Medecine, Kentucky, USA
| | - David W. Hein
- Department of Pharmacology and Toxicology and James Graham Brown Center, University of Louisville School of Medecine, Kentucky, USA
| | - Edith Sim
- Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK
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Merrick BA. Toxicoproteomics: Correlating Tissue and Serum Proteomics in Liver Injury. Clin Proteomics 2008. [DOI: 10.1002/9783527622153.ch24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
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Fukino K, Sasaki Y, Hirai S, Nakamura T, Hashimoto M, Yamagishi F, Ueno K. Effects of N-acetyltransferase 2 (NAT2), CYP2E1 and Glutathione-S-transferase (GST) genotypes on the serum concentrations of isoniazid and metabolites in tuberculosis patients. J Toxicol Sci 2008; 33:187-95. [DOI: 10.2131/jts.33.187] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Affiliation(s)
- Katsumi Fukino
- Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University
- Laboratory of Clinical Pharmacology, Faculty of Pharmacy, Chiba Institute of Science
| | - Yuka Sasaki
- Department of Thoracic Disease, National Hospital Organization Chiba-East National Hospital
| | - Shigekazu Hirai
- Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University
| | - Takayuki Nakamura
- Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University
| | - Masayo Hashimoto
- Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University
| | - Fumio Yamagishi
- Department of Thoracic Disease, National Hospital Organization Chiba-East National Hospital
| | - Koichi Ueno
- Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University
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Pal R, Rana SV, Vaiphei K, Singh K. Isoniazid-rifampicin induced lipid changes in rats. Clin Chim Acta 2007; 389:55-60. [PMID: 18157944 DOI: 10.1016/j.cca.2007.11.028] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2007] [Revised: 11/23/2007] [Accepted: 11/24/2007] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Isoniazid (INH) and rifampicine (RIF) continues to be highly effective drugs in the chemoprophylaxis and treatment of tuberculosis. It is associated with hepatotoxicity in some individuals. Change in liver and serum lipids may be one of the reasons of hepatotoxicity. We examined isoniazid-rifampicine induced lipid changes in liver and serum of rats. METHODS In a rat model of INH-RIF induced hepatotoxicity we evaluated the effect of oral administration of INH-RIF (50 mg/kg body weight /day each) on hepatic marker enzymes, total lipids, cholesterol, triglycerides and phospholipids in serum and liver of experimental rats after 28 days. Enzymes, total lipids and lipid fractions were measured according to standard methods. RESULTS Treatment with INH-RIF increased the hepatic marker enzymes after 28 days and altered the lipid levels in serum and liver. Administration of INH-RIF resulted in significantly increased liver and serum cholesterol and total Lipids as compared to control group, while triglycerides were significantly elevated in liver only. In contrast, phospholipids were significantly decreased in liver and no effect in serum was observed. CONCLUSION Changes in lipids (both in serum and liver) are likely involved in the pathogenesis of INH-RIF induced hepatoxicity in rats.
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Affiliation(s)
- R Pal
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Vivekanandan P, Gobianand K, Priya S, Vijayalakshmi P, Karthikeyan S. Protective effect of picroliv against hydrazine-induced hyperlipidemia and hepatic steatosis in rats. Drug Chem Toxicol 2007; 30:241-52. [PMID: 17613009 DOI: 10.1080/01480540701375216] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
The protective effect of picroliv (PIC) obtained from Picrorhiza kurroa (family: Scrophulariaceae) against hydrazine (Hz)-induced hyperlipidemia was evaluated in rats. Hz administration (50 mg/kg, i.p.) caused an increase in triglyceride (TG), cholesterol (CHO), free fatty acids (FFA), and total lipids (TL) in both the plasma and liver tissue of rats accompanied by a fall in phospholipids (PL) in the liver tissue 24 h after its administration, indicating its hyperlipidemic property. The above abnormality was prevented by simultaneous treatment of PIC (50 mg/kg, p.o.) with Hz. Hz treatment also caused an increase in the mobility of TG and TL from adipose tissue, and these results indicate that Hz administration could cause hepatic steatosis by nonhepatocellular factors (such as mobilization of depot fats). This effect was also prevented by simultaneous treatment of PIC with Hz. PIC-alone treatment, however, did not produce any change in the status of all the lipid parameters evaluated in plasma, liver, and adipose tissues. These results indicate that increased mobilization of depot fats from adipose tissue may contribute to the development of hepatic steatosis in addition to decreased lipoprotein secretion, increased hepatic TG biosynthesis, and increased hepatic uptake of FFA. These have been reported as the mechanism responsible for the development of Hz-induced hepatic steatosis. PIC prevents Hz-induced hyperlipidemia, hepatic steatosis, and mobilization of lipids from depot fats, but the mechanism behind the protective effect of PIC remains to be elucidated.
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Affiliation(s)
- P Vivekanandan
- Department of Pharmacology and Environmental Toxicology, Dr. A. L. M. Postgraduate Institute of Basic Medical Sciences, University of Madras, Chennai, India
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Adhvaryu MR, Reddy N, Parabia MH. Effects of four Indian medicinal herbs on Isoniazid-, Rifampicin- and Pyrazinamide-induced hepatic injury and immunosuppression in guinea pigs. World J Gastroenterol 2007; 13:3199-205. [PMID: 17589898 PMCID: PMC4436605 DOI: 10.3748/wjg.v13.i23.3199] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate and compare the hepatoprotective and immunomodulatory effects of Curcuma longa (CL), Ocimum sanctum (OS), Tinospora cordifolia (TC) and Zizyphus mauritiana (ZM) on liver injury and immunosuppression induced by Isoniazid (INH), Rifampicin (RIF) and Pyrazinamide (PZA).
METHODS: Duncan Hartley guinea pigs, weighing 700-1050 g, were treated orally with 50 mg/kg of INH, 100 mg/kg of RIF and 300 mg/Kg of PZA for 21-d. 200 mg/kg (bw) of each herb crude extract was administered to the herb control group and 2-h previous to INH + RIF + PZA (AKT) doses to the Herb + AKT groups. Serum alanine aminotransferase (ALT), aspertate aminotransferase (AST) bilirubin and Alkaline Phosphatase (ALP) were assessed on d 0 and 21 in all the groups. Phagocytic % (P%), Phagocytic Index (PI) and Chemotactic Index (CI) were also measured as immunologic parameters. Histological analysis was carried out to assess injury to the liver.
RESULTS: The AKT treated control group showed hepatotoxicity as judged by elevated serum AST 5-fold, AST/ALT ratio 4-fold, ALP 2-fold and hepatological changes, such as focal necrosis, portal triaditis and steatosis. Immune function was suppressed as judged by decreased P% (51.67 ± 1.68 vs 40.61 ± 1.28, P < 0.01), PI (2.0725 ± 0.05 vs 0.61 ± 0.05, P < 0.001) and CI (1.8525 ± 0.04 vs 0.695 ± 0.07, P < 0.001). All four herb treated groups showed normal liver histology, enzyme levels and increased P%, while PI and CI were enhanced in the TC and ZM treated groups, respectively. CL + AKT, TC + AKT and ZM + AKT showed nearly normal histology with minimal inflammation and microvesicular steatosis, while OS + AKT showed partial protection. Hepatotoxicity was prevented by restricting the rise of AST by 2-fold in CL + AKT and TC + AKT groups and by 3-fold in OS + AKT and ZM + AKT groups, AST/ALT by 2-fold and ALP to normal levels in all four groups. All four herb + AKT groups showed normal to enhanced neutrophil function.
CONCLUSION: All four herbs showed hepatoprotective potential and prevented immunosuppression. CL and TC showed the highest hepatoprotective activity, while TC and ZM showed strong immunostimulatory activity.
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Affiliation(s)
- Meghna-R Adhvaryu
- Bapalal Vaidya Botanical Research Centre, Department of Biosciences, Veer Narmad South Gujarat University, 110, Nehru Nagar Society, Ichchhanath Road, Surat 395007, India.
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Lee MH, Hong I, Kim M, Lee BH, Kim JH, Kang KS, Kim HL, Yoon BI, Chung H, Kong G, Lee MO. Gene expression profiles of murine fatty liver induced by the administration of valproic acid. Toxicol Appl Pharmacol 2006; 220:45-59. [PMID: 17292431 DOI: 10.1016/j.taap.2006.12.016] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2006] [Revised: 12/13/2006] [Accepted: 12/13/2006] [Indexed: 11/26/2022]
Abstract
Valproic acid (VPA) has been used as anticonvulsants, however, it induces hepatotoxicity such as microvesicular steatosis and necrosis in the liver. To explore the mechanisms of VPA-induced steatosis, we profiled the gene expression patterns of the mouse liver that were altered by treatment with VPA using microarray analysis. VPA was orally administered as a single dose of 100 mg/kg (low-dose) or 1000 mg/kg (high-dose) to ICR mice and the animals were killed at 6, 24, or 72 h after treatment. Serum alanine aminotransferase and aspartate aminotransferase levels were not significantly altered in the experimental animals. However, symptoms of steatosis were observed at 72 h with low-dose and at 24 h and 72 h with high-dose. After microarray data analysis, 1910 genes were selected by two-way ANOVA (P<0.05) as VPA-responsive genes. Hierarchical clustering revealed that gene expression changes depended on the time rather than the dose of VPA treatment. Gene profiling data showed striking changes in the expression of genes associated with lipid, fatty acid, and steroid metabolism, oncogenesis, signal transduction, and development. Functional categorization of 1156 characteristically up- and down-regulated genes (cutoff >1.5-fold) revealed that 60 genes were involved in lipid metabolism that was interconnected with biological pathways for biosynthesis of triglyceride and cholesterol, catabolism of fatty acid, and lipid transport. This gene expression profile may be associated with the known steatogenic hepatotoxicity of VPA and it may provide useful information for prediction of hepatotoxicity of unknown chemicals or new drug candidates through pattern recognition.
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