Troglitazone and liver injury

Chojkier, Mario

doi:10.1002/hep.20567

Cited by 113 publications

(62 citation statements)

References 159 publications

(226 reference statements)

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“…A variety of hypotheses were proposed, including reactive metabolite formation and accumulation, mitochondrial dysfunction and oxidative stress, inhibition of bile salt exporter pump, and apoptosis (Chojkier, 2005;Masubuchi, 2006). The major TGZ metabolites (sulfate, glucuronide, quinone) have been identified in cultured cells, experimental animals, and human patients (Kawai et al, 1997;Loi et al, 1999;Yoshigae et al, 2000;Honma et al, 2002;Watanabe et al, 2002).…”

Section: B Example: Troglitazonementioning

confidence: 99%

Inflammatory Stress and Idiosyncratic Hepatotoxicity: Hints from Animal Models

et al. 2009

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Section: B Example: Troglitazonementioning

confidence: 99%

Inflammatory Stress and Idiosyncratic Hepatotoxicity: Hints from Animal Models

et al. 2009

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“…They are one of the leading causes for drug development failures and removal of medicines from the market. A well known example is troglitazone, which was removed from the market by the Food and Drug Administration in 2000, because of its potential to cause idiosyncratic liver injury (Chojkier, 2005). IADRs appear to be independent of dose, and the onset of injury varies relative to the onset of drug treatment.…”

mentioning

confidence: 99%

Modest Inflammation Enhances Diclofenac Hepatotoxicity in Rats: Role of Neutrophils and Bacterial Translocation

Deng

Stachlewitz

Liguori

et al. 2006

J Pharmacol Exp Ther

136

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Idiosyncratic adverse drug reactions (IADRs) represent an important human health problem, yet animal models for preclinical prediction of these reactions are lacking. Recent evidence in animals suggests that some IADRs arise from drug interaction with an inflammatory episode that renders the liver sensitive to injury. Diclofenac (DCLF) is one of those drugs for which the clinical use is limited by idiosyncratic liver injury. We tested the hypothesis that modest inflammation triggered in rats by a small dose of lipopolysaccharide (LPS) renders a nonhepatotoxic dose of DCLF injurious to liver. Cotreatment of rats with nonhepatotoxic doses of LPS and DCLF resulted in elevated serum alanine aminotransferase activity and liver histopathologic changes 6 h after DCLF administration. Neither LPS nor DCLF alone had such an effect. Gene array analysis of livers revealed a unique gene expression pattern in the LPS/DCLFcotreated group compared with groups given either agent alone. Antiserum-induced neutrophil (PMN) depletion in LPS/ DCLF-cotreated rats protected against liver injury, demonstrating a role for PMNs in the pathogenesis of this LPS/DCLF interaction. Gut sterilization of LPS/DCLF-treated rats did not protect against liver injury. In contrast, gut sterilization did attenuate liver injury caused by a large, hepatotoxic dose of DCLF, suggesting that hepatotoxicity induced by large doses of DCLF is caused in part by its ability to increase intestinal permeability to endotoxin or other bacterial products. These results demonstrate that inflammation-DCLF interaction precipitates hepatotoxicity in rats and raise the possibility of creating animal models that predict human IADRs.

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“…Troglitazone (TGZ) is an anti-diabetic drug that was withdrawn from the market due to acute severe idiosyncratic drug-induced liver injury in some patients [69][70][71]. Clinical observations and in vivo rat studies suggested, at least in part, a cholestatic mechanism for TGZ-induced hepatotoxicity, in addition to a role of a reactive quinone metabolite [72,73].…”

Section: Bile Acids As Key Players In Dilimentioning

confidence: 99%

Bile acids in drug induced liver injury: Key players and surrogate markers

Schadt

Wolf

Philippe

et al. 2016

Clinics and Research in Hepatology and Gastroenterology

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Bile acid research has gained great momentum since the role of bile acids as key signaling molecules in the enterohepatic circulation was discovered. Their physiological function in regulating their own homeostasis, as well as energy and lipid metabolism make them interesting targets for the pharmaceutical industry in the context of diseases such as bile acid induced diarrhea, bile acid induced cholestasis or nonalcoholic steatohepatitis. Changes in bile acid homeostasis are also linked to various types of drug-induced liver injury (DILI). However, the key question whether bile acids are surrogate markers for monitoring DILI or key pathogenic players in the onset and progression of DILI is under intense investigation. The purpose of this review is to summarize the different facets of bile acids in the context of normal physiology, hereditary defects of bile acid transport and DILI.

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Troglitazone and liver injury

Cited by 113 publications

References 159 publications

Inflammatory Stress and Idiosyncratic Hepatotoxicity: Hints from Animal Models

Inflammatory Stress and Idiosyncratic Hepatotoxicity: Hints from Animal Models

Modest Inflammation Enhances Diclofenac Hepatotoxicity in Rats: Role of Neutrophils and Bacterial Translocation

Bile acids in drug induced liver injury: Key players and surrogate markers

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