The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Minhan Tan - One of the best experts on this subject based on the ideXlab platform.
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patient specific hepatocyte like cells derived from induced pluripotent stem cells model pazopanib mediated Hepatotoxicity
Scientific Reports, 2017Co-Authors: Yukti Choudhury, Yichin Toh, Jiangwa Xing, Jonathan Poh, Hui Shan Tan, Ravindran Kanesvaran, Minhan TanAbstract:Idiosyncratic drug-induced Hepatotoxicity is a major cause of liver damage and drug pipeline failure, and is difficult to study as patient-specific features are not readily incorporated in traditional Hepatotoxicity testing approaches using population pooled cell sources. Here we demonstrate the use of patient-specific hepatocyte-like cells (HLCs) derived from induced pluripotent stem cells for modeling idiosyncratic Hepatotoxicity to pazopanib (PZ), a tyrosine kinase inhibitor drug associated with significant Hepatotoxicity of unknown mechanistic basis. In vitro cytotoxicity assays confirmed that HLCs from patients with clinically identified Hepatotoxicity were more sensitive to PZ-induced toxicity than other individuals, while a prototype hepatotoxin acetaminophen was similarly toxic to all HLCs studied. Transcriptional analyses showed that PZ induces oxidative stress (OS) in HLCs in general, but in HLCs from susceptible individuals, PZ causes relative disruption of iron metabolism and higher burden of OS. Our study establishes the first patient-specific HLC-based platform for idiosyncratic Hepatotoxicity testing, incorporating multiple potential causative factors and permitting the correlation of transcriptomic and cellular responses to clinical phenotypes. Establishment of patient-specific HLCs with clinical phenotypes representing population variations will be valuable for pharmaceutical drug testing.
Yukti Choudhury - One of the best experts on this subject based on the ideXlab platform.
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patient specific hepatocyte like cells derived from induced pluripotent stem cells model pazopanib mediated Hepatotoxicity
Scientific Reports, 2017Co-Authors: Yukti Choudhury, Yichin Toh, Jiangwa Xing, Jonathan Poh, Hui Shan Tan, Ravindran Kanesvaran, Minhan TanAbstract:Idiosyncratic drug-induced Hepatotoxicity is a major cause of liver damage and drug pipeline failure, and is difficult to study as patient-specific features are not readily incorporated in traditional Hepatotoxicity testing approaches using population pooled cell sources. Here we demonstrate the use of patient-specific hepatocyte-like cells (HLCs) derived from induced pluripotent stem cells for modeling idiosyncratic Hepatotoxicity to pazopanib (PZ), a tyrosine kinase inhibitor drug associated with significant Hepatotoxicity of unknown mechanistic basis. In vitro cytotoxicity assays confirmed that HLCs from patients with clinically identified Hepatotoxicity were more sensitive to PZ-induced toxicity than other individuals, while a prototype hepatotoxin acetaminophen was similarly toxic to all HLCs studied. Transcriptional analyses showed that PZ induces oxidative stress (OS) in HLCs in general, but in HLCs from susceptible individuals, PZ causes relative disruption of iron metabolism and higher burden of OS. Our study establishes the first patient-specific HLC-based platform for idiosyncratic Hepatotoxicity testing, incorporating multiple potential causative factors and permitting the correlation of transcriptomic and cellular responses to clinical phenotypes. Establishment of patient-specific HLCs with clinical phenotypes representing population variations will be valuable for pharmaceutical drug testing.
Richard Dekhuijzen - One of the best experts on this subject based on the ideXlab platform.
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antituberculosis drug induced Hepatotoxicity concise up to date review
Journal of Gastroenterology and Hepatology, 2008Co-Authors: Alma Tostmann, Martin J Boeree, Rob E Aarnoutse, Wiel C M De Lange, Andre J A M Van Der Ven, Richard DekhuijzenAbstract:The cornerstone of tuberculosis management is a 6-month course of isoniazid, rifampicin, pyrazinamide and ethambutol. Compliance is crucial for curing tuberculosis. Adverse effects often negatively affect the compliance, because they frequently require a change of treatment, which may have negative consequences for treatment outcome. In this paper we review the incidence, pathology and clinical features of antituberculosis drug-induced Hepatotoxicity, discuss the metabolism and mechanisms of toxicity of isoniazid, rifampicin and pyrazinamide, and describe risk factors and management of antituberculosis drug-induced Hepatotoxicity. The reported incidence of antituberculosis drug-induced Hepatotoxicity, the most serious and potentially fatal adverse reaction, varies between 2% and 28%. Risk factors are advanced age, female sex, slow acetylator status, malnutrition, HIV and pre-existent liver disease. Still, it is difficult to predict what patient will develop Hepatotoxicity during tuberculosis treatment. The exact mechanism of antituberculosis drug-induced Hepatotoxicity is unknown, but toxic metabolites are suggested to play a crucial role in the development, at least in the case of isoniazid. Priorities for future studies include basic studies to elucidate the mechanism of antituberculosis drug-induced Hepatotoxicity, genetic risk factor studies and the development of shorter and safer tuberculosis drug regimens.
Sooyoun Lee - One of the best experts on this subject based on the ideXlab platform.
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genetic polymorphisms of nat2 and cyp2e1 associated with antituberculosis drug induced Hepatotoxicity in korean patients with pulmonary tuberculosis
Tuberculosis, 2007Co-Authors: Hyunjung Cho, Wonjung Koh, Yon Ju Ryu, Myung Hyun Nam, Jongwon Kim, Sooyoun LeeAbstract:Antituberculosis drug-induced hepatitis attributed to isoniazid (INH) is one of the most prevalent drug-induced liver injuries. INH is metabolized by hepatic N-acetyltransferase (NAT) and cytochrome P450 2E1 (CYP2E1) to form hepatotoxins. The aim of this study was to evaluate whether polymorphisms of the NAT2 and/or CYP2E1 genes were associated with antituberculosis drug-induced Hepatotoxicity in Korean patients. A total of 132 patients with tuberculosis who received antituberculosis treatment were followed prospectively. Their NAT2 and CYP2E1 genotypes were determined using polymerase chain reaction (PCR) with or without sequencing. Eighteen (13.6%) patients developed antituberculosis drug-induced Hepatotoxicity. Regarding NAT2, slow acetylators had a higher incidence of Hepatotoxicity than rapid acetylators (36.8% vs. 9.7%, P=0.005) and there was a 3.8-fold risk of Hepatotoxicity for the slow acetylators compared to the rapid acetylators. For the CYP2E1 gene, the RsaI polymorphism in the 5' untranslated region, and a polymorphic repetitive sequence at the CYP2E1 5'-flaking region were analyzed; there was no significant association between any CYP2E1 genotype and antituberculosis drug-induced Hepatotoxicity. In conclusion, slow acetylator status of NAT2 was a significant susceptibility risk factor for antituberculosis drug-induced Hepatotoxicity; NAT2 genotyping may be a useful tool for predicting antituberculosis drug-induced Hepatotoxicity.
Vincent Lebot - One of the best experts on this subject based on the ideXlab platform.
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Contaminant Hepatotoxins as Culprits for Kava Hepatotoxicity - Fact or Fiction?
Phytotherapy research : PTR, 2012Co-Authors: Rolf Teschke, Jerome Sarris, Vincent LebotAbstract:The culprit of kava Hepatotoxicity will continue to remain a mystery in humans, if the underlying reaction is of idiosyncratic, unpredictable, and dose-independent nature due potentially to some metabolic aberration in a few individuals emerging from kava use. In addition, kava Hepatotoxicity is presently not reproducible experimentally in preclinical models, as demonstrated by studies showing whole kava extracts are not hepatotoxic. This led us to propose our ‘working hypothesis’ that contaminant hepatotoxins including moulds might have caused rare kava Hepatotoxicity in humans. Further studies are now warranted to proof or disproof our working hypothesis, because kava Hepatotoxicity possibly based on contaminant hepatotoxins could be a preventable disease. In the meantime, however, for minimizing toxicity risk in kava users, a pragmatic approach should focus on the medicinal use of an aqueous extract derived from peeled rhizomes and roots of a non-mouldy noble kava cultivar, limited to maximum 250-mg kavalactones daily for acute or intermittent use. Copyright © 2012 John Wiley & Sons, Ltd.
