title: Drug-induced idiosyncratic hepatotoxicity: prevention strategy developed after the troglitazone case.
abstract: Troglitazone induced an idiosyncratic, hepatocellular injury-type hepatotoxicity in humans. Statistically, double null genotype of glutathione S-transferase isoforms, GSTT1 and GSTM1, was a risk factor, indicating a low activity of the susceptible patients in scavenging chemically reactive metabolites. CYP3A4 and CYP2C8 were involved in the metabolic activation and CYP3A4 was inducible by repeated administrations of troglitazone. The genotype analysis, however, indicated that the metabolic idiosyncrasy resides in the degradation of but not in the production of the toxic metabolites of troglitazone. Antibody against hepatic aldolase B was detected in the case patients, suggesting involvement of immune reaction in the toxic mechanism. Troglitazone induced apoptotic cell death in human hepatocytes at a high concentration, and this property may have served as the immunological danger signal, which is thought to play an important role in activating immune reactions. Hypothesis is proposed in analogy to the virus-induced hepatitis. After the troglitazone-case, pharmaceutical companies implemented screening systems for chemically reactive metabolites at early stage of drug development, taking both the amount of covalent binding to the proteins in vitro and the assumed clinical dose level into consideration. At the post-marketing stage, gene analyses of the case patients, if any, to find pharmacogenetic biomarkers could be a powerful tool for contraindicating to the risky patients.
authors.affiliation: Yokohama College of Pharmacy, Yokohama, Japan. toshihiko_ikeda-san@nifty.com
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Ikeda
mesh_terms: D000328:Adult; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001711:Biotransformation / Q000235:genetics; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology / Q000517:prevention & control*; D002839:Chromans / Q000009:adverse effects* / Q000378:metabolism; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis; D005260:Female; D005805:Genes, MHC Class I / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D056737:Safety-Based Drug Withdrawals; D045162:Thiazolidinediones / Q000009:adverse effects* / Q000378:metabolism; D000077288:Troglitazone
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; D002839:Chromans; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; D005982:Glutathione Transferase; D045162:Thiazolidinediones; D000077288:Troglitazone; C450259:CYP2C8 protein, human; C510163:CYP3A4 protein, human; C413545:glutathione S-transferase T1