Review
Drug-Induced Idiosyncratic Hepatotoxicity: Prevention Strategy Developed after the Troglitazone Case

https://doi.org/10.2133/dmpk.DMPK-10-RV-090Get rights and content

Summary:

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 virusinduced 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.

References (62)

  • T. Watanabe et al.

    Was it not possible to predict liver dysfunction caused by troglitazone during the nonclinical safety studies?

    Reevaluation of safety. Iyakuhin Kenkyu

    (1999)
  • T. Yokoi

    Troglitazone. Handb. Exp. Pharmacol.

    (2010)
  • H.J. Zimmerman

    Various forms of chemically induced liver injury and their detection by diagnostic procedures

    Environ. Health Perspect.

    (1976)
  • Z.X. Liu et al.

    Role of innate immunity in acetaminophen-induced hepatotoxicity

    Expert Opin. Drug Metab. Toxicol.

    (2006)
  • D. Vergani et al.

    Antibodies to the surface of halothane-altered rabbit hepatocytes in patients with severe halothane-associated hepatitis

    N. Engl. J. Med.

    (1980)
  • K. Kawai et al.

    Disposition and metabolism of the new oral antidiabetic drug troglitazone in rats, mice and dogs

    Arzneimittelforschung

    (1997)
  • K. Kassahun et al.

    Studies on the metabolism of troglitazone to reactive intermediates in vitro and in vivo. Evidence for novel biotransformation pathways involving quinone methide formation and thiazolidinedione ring scission

    Chem. Res. Toxicol.

    (2001)
  • K. He et al.

    Metabolic activation of troglitazone: identification of a reactive metabolite and mechanisms involved

    Drug Metab. Dispos.

    (2004)
  • H. Sato et al.

    Covelent adducts in human primary hepatocytes cultured with ª14C]troglitazone

    Drug Metab. Rev.

    (2000)
  • J. Gan et al.

    Troglitazone thiol adduct formation in human liver microsomes: enzyme kinetics and reaction phenotyping

    Drug Metab. Lett.

    (2008)
  • V. Ramachandran et al.

    Troglitazone increases cytochrome P-450 3A protein and activity in primary cultures of human hepatocytes

    Drug Metab. Dispos.

    (1999)
  • J. Sahi et al.

    Effect of troglitazone on cytochrome P450 enzymes in primary cultures of human and rat hepatocytes

    Xenobiotica

    (2000)
  • C.M. Loi et al.

    Effect of troglitazone on the pharmacokinetics of an oral contraceptive agent

    J. Clin. Pharmacol.

    (1999)
  • P. Frantz et al.

    Rezulin (troglitazone) greatly increases cyclosporine metabolism

    J. Heart Lung Transplant.

    (1998)
  • M.H. Park et al.

    Troglitazone, a new antidiabetic agent, decreases cyclosporine level

    J. Heart Lung Transplant.

    (1998)
  • J.R. Koup et al.

    Effect of troglitazone on urinary excretion of 6β-hydroxycortisol

    J. Clin. Pharmacol.

    (1998)
  • I. Watanabe et al.

    A study to survey susceptible genetic factors responsible for troglitazone-associated hepatotoxicity in Japanese patients with type 2 diabetes mellitus

    Clin. Pharmacol. Ther.

    (2003)
  • M.I. Lucena et al.

    Glutathione S-transferase m1 and t1 null genotypes increase susceptibility to idiosyncratic drug-induced liver injury

    Hepatology

    (2008)
  • R. Okada et al.

    Direct and rapid genotyping of glutathione-S-transferase M1 and T1 from human blood specimens using the SmartAmp2 method

    Drug Metab. Dispos.

    (2010)
  • W.H. Chung et al.

    Medical genetics: a marker for Stevens-Johnson syndrome

    Nature

    (2004)
  • S.I. Hung et al.

    HLAB*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol

    Proc. Natl. Acad. Sci. U.S.A.

    (2005)
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