The Mechanistic Role of Mitochondrial Oxidative stress in Troglitazone - Induced Apoptosis in Human Hepatocytes

Abstract

Troglitazone (TGZ), a thiazolidinedione anti-diabetic drug, was withdrawn from the market due to reported cases of serious idiosyncratic hepatotoxicity. Although the clinical features suggest metabolic idiosyncrasy rather than immunoallergic reactions, the role of reactive metabolites in TGZ-induced toxicity has remained controversial. Besides producing reactive intermediates, TGZ is also known to induce oxidative stress in hepatocytes. However, the signaling pathways bridging reactive oxygen species (ROS) production and apoptosis remains unresolved. This study aims to elucidate the causative role of toxic metabolites and the MAPK pathway in a metabolically competent human hepatocyte cell line of non- tumorigenic origin (HC-04). The data indicate that mitochondrial oxidative stress, as well as thioredoxin-2 (Trx-2) and apoptosis signal-regulating kinase 1 (ASK1) are involved in upstream events of TGZ-induced apoptosis. Elucidation of these pathways may not only open new ways for therapeutic intervention but also aid in the development of safer analogs.