Hepatocellular Toxicity of Imidazole and Triazole Antimycotic Agents
Hepatotoxicity has been described for all antimycotic azoles currently marketed. A possible mechanism involving mitochondrial dysfunction has been postulated for ketoconazole, but not for the other azoles. The aim of the current investigations was to study the toxicity of different azoles in human cell models and to find out mechanisms of their toxicity. In HepG2 cells, posaconazole and ketoconazole were cytotoxic starting at 20 and 50 μM and decreased the cellular ATP content starting at 5 and 10 μM, respectively. In HepaRG cells, cytotoxicity started at 20 and 100 μM for posaconazole and ketoconazole, respectively, and was slightly accentuated by cytochrome P450 3A4 induction with rifampicin and 1A2 with 3-methylcholantrene. Voriconazole and fluconazole were not cytotoxic. In isolated mouse liver mitochondria, ketoconazole impaired membrane potential and complex I activity, whereas the other azoles were not toxic. In HepG2 cells exposed for 24 h, both posaconazole and ketoconazole (but not fluconazole or voriconazole) decreased the mitochondrial membrane potential, impaired the function of enzyme complexes of the electron transport chain, were associated with mitochondrial superoxide accumulation, decreased mitochondrial DNA and induced apoptosis. In HepG2 cells with mitochondrial dysfunction induced by the vitamin B12 antagonist hydroxy-cobalamin[c-lactam], cytotoxicity and/or ATP depletion was more accentuated than in untreated cells. We conclude that ketoconazole and posaconazole are mitochondrial toxicants starting at concentrations, which can be reached in vivo. Cytotoxicity and ATP depletion are more accentuated in cells with mitochondrial damage, suggesting that preexisting mitochondrial dysfunction is a susceptibility factor for hepatotoxicity associated with these drugs.