To determine whether
cytochrome P450 proteins were differentially altered in severe chronic
liver diseases, we examined 50 livers removed at
liver transplantation from patients with end-stage
cirrhosis, including 18 with and 32 without
cholestasis, and compared the results with 21 histologically normal livers.
NADPH-cytochrome c reductase activities were unaltered in microsomes from cirrhotic livers. Total
cytochrome P450 content was significantly reduced. The catalytic activities of four
xenobiotic-metabolizing P450s and the level of the corresponding
proteins were differentially altered. Thus, P450 3A-supported
testosterone 6 beta-hydroxylase activity and 3A
protein appeared to be reduced, but only in the subgroup without
cholestasis was this change significant. In contrast, 2E1 and the related N,N-
dimethylnitrosamine N-demethylase activity were clearly reduced in livers from patients with cholestatic forms of
cirrhosis but appeared not to be changed in other cirrhotic livers. Similarly, P450 2C
protein was reduced only in patients with severe chronic
cholestasis. Finally, P450 1A2 and 1A2-supported
ethoxyresorufin O-deethylase activity were significantly reduced in hepatic microsomes from patients with both types of advanced
liver disease. In summary, these data demonstrate that
cytochrome P450 proteins are selectively altered in severe chronic
liver disease, some being profoundly decreased, others less so or not at all. Our results also suggest that there may be different patterns of altered hepatic P450 expression according to the presence or absence of
cholestasis in patients with
cirrhosis severe enough to require
transplantation.