Differential alteration of cytochrome P450 isoenzymes in two experimental models of cirrhosis

Liver diseases are associated with a decrease in hepatic drug elimination, but there is evidence that cirrhosis does not result in uniform changes of cytochrome P450 (CYP) isoenzymes. The objective of this study was to determ ine the content and activity of four CYP isoenzymes in the bile duct ligati on and carbon tetrachloride (CCl4)-induced models of cirrhosis. The hepatic content of CYP1A, CYP2C, CYP2E1, and CYP3A was measured by Western blot an alysis. CYP activity in vivo was evaluated with breath tests using substrat es specific for different isoenzymes: caffeine (CYP1A2), aminopyrine (CYP2C 11), nitrosodimethylamine (CYP2E1), and erythromycin (CYP3A). Bile duct lig ation resulted in biliary cirrhosis; CYP1A, CYP2C and CYP3A content was dec reased and the caffeine, aminopyrine, and erythromycin breath tests were re duced whereas CYP2E1 content and the nitrosodimethylamine breath test were unchanged compared with controls. CCl4 treatment resulted in cirrhosis of v arying severity as assessed from the decrease in liver weight and serum alb umin. In rats with mild cirrhosis, CYP content was comparable with controls except for a decrease in CYP2C. The activity of CYPs was also unchanged ex cept for an increase in CYP2E1 activity. In rats with more severe cirrhosis , the content of all four CYP isoenzymes and the caffeine, aminopyrine, and erythromycin breath tests were reduced whereas the nitrosodimethylamine br eath test was unchanged. In both models of cirrhosis, there was a significa nt correlation between the breath tests results and the severity of cirrhos is as assessed from serum albumin levels. These results indicate that conte nt and the catalytic activity of individual CYP enzymes are differentially altered by cirrhosis in the rat and also suggest that drug probes could be useful to assess hepatic functional reserve.