Ursodeoxycholic acid prevents hepatic cytochrome P450 isozyme reduction inrats with deoxycholic acid-induced liver injury

Background/Aims: Hydrophobic bile acids, such as deoxycholic acid produce c holestatic liver injury. Ursodeoxycholic acid has been shown to be useful i n the treatment of cholestatic liver disease. Methods: In this study, we investigated the effects of deoxycholic acid or ursodeoxycholic acid (1% of diet, for 14 days) and their combination (1% ea ch) on expression of hepatic cytochrome P450 isozymes, their related enzyme activities and mRNA level in rats. Results: Adding 1% deoxycholic acid to chow caused a marked increase in ser um total bilirubin (47-fold) and total bile acid (8-fold) concentrations an d in alkaline phosphatase (2.5-fold, p<0.01) and alanine aminotransferase a ctivities (23.5-fold, p<0.01). Adding the same dose of ursodeoxycholic acid along with the deoxycholic acid mitigated both the rise in serum total bil irubin and bile acid concentrations and that in alkaline phosphatase and al anine aminotransferase activities, although the use of ursodeoxycholic acid alone did not affect any of the above. Feeding 1% deoxycholic acid caused a decrease (48% of control) in total cytochrome P450 content in hepatic mic rosomes. Addition of 1% ursodeoxycholic acid along with the 1% deoxycholic acid completely prevented the decrease in total cytochrome P450 content. Fe eding ursodeoxycholic acid alone did not affect the total cytochrome P450 c ontent, The expression of cytochrome P450 2B1, 2E1, 3A2, 2C6, 2C11 and 4A1 proteins in hepatic microsomes was decreased by deoxycholic acid (44, 51, 2 3, 59, 30 and 74% of control, respectively). Likewise, the activities of cy tochrome P450 2B1 (pentoxyresorufin O-depentylation), 2E1 (aniline p-hydrox ylation) and 3A2 (testosterone 6 beta-hydroxyIation) isozymes and the 3A2 m RNA levels in liver were decreased by deoxycholic acid. Addition of 1% urso deoxycholic acid to 1% deoxycholic acid also prevented the decrease in thes e cytochrome P450 proteins, related enzyme activities and mRNA levels in li ver. Conclusions: These results indicate that, in rats with deoxycholic acid-ind uced liver injury, ursodeoxycholic acid prevents the decrease in hepatic cy tochrome P450 isozymes and suggest that ursodeoxycholic acid is useful for the treatment of liver injury in terms of aiding the normalization of the h epatic drug-metabolizing system.