Premium
Differential alterations of cytochrome P450 proteins in livers from patients with severe chronic liver disease
Author(s) -
George Jacob,
Murray Michael,
Byth Karen,
Farrell Geoffrey C.
Publication year - 1995
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.1840210121
Subject(s) - cholestasis , cirrhosis , cytochrome p450 , medicine , liver disease , microsome , endocrinology , liver transplantation , biology , chronic liver disease , transplantation , enzyme , metabolism , biochemistry
Abstract 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 6β‐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. (Hepatology 1995;21:120‐128).