Troglitazone-Induced Hepatic Necrosis in an Animal Model of Silent Genetic Mitochondrial Abnormalities

Abstract

Troglitazone, a first-generation thiazolidinedione antidiabetic drug, was withdrawn from the market due to an unacceptable risk of idiosyncratic hepatotoxicity. Troglitazone does not cause hepatotoxicity in normal healthy rodents, but it produces mitochondrial injury in vitro at high concentrations. The aim of this study was to explore whether genetic mitochondrial abnormalities might sensitize mice to hepatic adverse effects of troglitazone. We used heterozygous superoxide dismutase 2 (Sod2(+/-)) mice as a model of clinically silent mitochondrial stress. Troglitazone was daily administered for 4 weeks (0, 10 or 30 mg/kg/day, ip). We found that troglitazone caused overt liver injury in the high-dose group, manifested by increased serum alanine aminotransferase activity (> twofold) and midzonal areas of hepatic necrosis, in Sod2(+/-) but not in wild-type mice. No signs of hepatotoxicity were apparent at 2 weeks of treatment. Hepatic mitochondria isolated from troglitazone-treated mice exhibited decreased activities of aconitase (by 45%) and complex I (by 46%) and increased (by 58%) protein carbonyls, indicative of enhanced mitochondrial oxidant stress. This was paralleled by compensatory increases in mitochondrial glutathione levels. Finally, in hepatocytes isolated from untreated Sod2(+/-), but not wild-type mice, troglitazone caused a concentration-dependent increase in superoxide anion levels as demonstrated with a selective mitochondria-targeting fluorescent probe. In conclusion, prolonged administration of troglitazone can superimpose oxidant stress, potentiate mitochondrial damage, and induce delayed hepatic necrosis in mice with genetically compromised mitochondrial function. These data are consistent with our hypothesis that inherited or acquired mitochondrial abnormalities may be one of the contributing determinants of susceptibility to troglitazone-induced idiosyncratic liver injury.

Mitochondrial dysfunction and delayed hepatotoxicity: another lesson from troglitazone

“…These mitochondrial changes were inhibited by N-acetyl cysteine [15]. Furthermore, enhanced susceptibility to cell injury in conditions of preexisting oxidative stress/mitochondrial impairment has been demonstrated by Ong and Boelsterli in a mouse model of silent mitochondrial abnormality [44]. This is relevant to patients with pre-existing oxidative stress due to NAFLD or glutathione depletion.…”

“…Many techniques are currently available [9,10]. The use of better animal models that replicate the human disease phenotype [44,64] could also unmask latent toxic potentials.…”

Mitochondrial Superoxide Dismutase and Glutathione Peroxidase in Idiosyncratic Drug-Induced Liver Injury

“…The role of SOD2 in drug-induced hepatotoxicity has proven contradictory. Ong and coworkers 19 reported that Sod2 þ/À knockout mice developed increased serum alanine aminotransferase activity and hepatic necrosis after prolonged troglitazone administration. However, Fujimoto and coworkers 20 were unable to reproduce these results.…”

Clinical Syndromes and Consequences of Antiretroviral-Related Hepatotoxicity5, 1, 3

“…Following exposure, the toxic moiety induces some type of stress or functional disturbance, with mitochondrial injury being one of the most important targets recognized. 21,22 A number of adaptation mechanisms are then initiated to counteract the inflicted damage. 23,24 In addition, innate and adaptive immune responses are other factors of interest which determine the progression and severity of liver injury.…”