Host: The Japanese Society of Toxicology
Name : The 50th Annual Meeting of the Japanese Society of Toxicology
Date : June 19, 2023 - June 21, 2023
Mitochondrial toxicity and bile acid accumulation in hepatocytes are the main mechanisms of drug-induced liver injury (DILI), and both are thought to promote hepatocyte stress and induce cell death or immune and inflammatory responses. In this study, we aimed to clarify the interaction between bile acids and drugs using isolated mice liver mitochondria. Both deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA), which are highly cytotoxic, induced mitochondrial swelling. This swelling was very weak under calcium-free experimental conditions and was suppressed by cyclosporine, a specific inhibitor of PTP-dependent mitochondrial swelling. DCA also inhibited state3 respiratory activity and decreased the state3/state4 ratio. In experiments on the interaction between DCA and DILI drugs, DCA enhanced mitochondrial swelling induced by troglitazone, a potent inhibitor of bile salt export pump (BSEP/ABCB11), and more markedly enhanced mitochondrial swelling induced by diclofenac. Weakly cytotoxic cholic acid (CA) alone had no effect on swelling or respiratory activity and had no apparent potentiating effect on swelling induced by DILI drugs. These results indicate that bile acids directly potentiate drug-induced mitochondrial toxicity.
