Changes in coumarin kinetics and subcellular localization of CYP2E1 contribute to bile duct damage and reduce hepatocellular damage after repeated administration of coumarin in rats

Coumarin exhibits different hepatotoxicity in rats depending on the administration frequency. To investigate the underlying mechanisms for the differences, we administered coumarin to rats as a single dose or repeatedly for 4 weeks. We found large increases in blood levels of liver enzymes and noticeable centrilobular hepatic necrosis after a single dose of coumarin. After repeated administration, enzyme levels mildly increased, while those of γ-GTP and total bilirubin significantly increased, suggesting bile duct damage. In the control group, cytochrome P450 2E1 (CYP2E1) showed a diffuse subcellular distribution but accumulated within the hepatocyte endoplasmic reticulum after repeated coumarin administration. The maximum blood concentrations of coumarin and its metabolites were significantly lower upon repeated administration. The results suggest that changes in coumarin pharmacokinetics and CYP2E1 subcellular distribution contribute to resistance to coumarin-induced hepatic necrosis, while cytotoxicity of metabolic conjugates shown in vitro may contribute to bile duct damage upon repeated coumarin administration.