Selective reduction of hepatic cytochrome P450 content in patients with intrahepatic cholestasis. A mechanism for impairment of microsomal drug oxidation.
Alteration of the components of the mixed-function oxidase system, including cytochrome P450, cytochrome b5, cytochrome P450 reductase, and cytochrome b5 reductase, was examined in liver microsomes prepared from needle biopsy samples of 12 patients with intrahepatic cholestasis. The rate of p-nitroanisole O-demethylation in the microsomes was also measured as the activity of cytochrome P450-dependent drug oxidation. The cytochrome P450 content (0.29 +/- 0.05 nmol/mg microsomal protein) in the patients was significantly lower than that in the 11 control subjects (0.41 +/- 0.09). The rate of p-nitroanisole O-demethylation was also significantly lower in the patients. However, the cytochrome b5 content and the activities of the reduced forms of nicotinamide adenine dinucleotide phosphate- and nicotinamide adenine dinucleotide-cytochrome c reductases did not differ between the two groups. Thus, selective reduction of cytochrome P450 seems to play a major role in the impairment of microsomal drug oxidation during intrahepatic cholestasis. Moreover, the reduction of cytochrome P450 was correlated with the serum concentrations of total bilirubin and bile acid but not with the serum glutamic oxaloacetic transaminase value. These observations suggest that the reduction of cytochrome P450 might be related to the severity of cholestasis.
D000328:Adult; D001647:Bile Acids and Salts / Q000097:blood; D001663:Bilirubin / Q000097:blood; D002780:Cholestasis, Intrahepatic / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism*
D001647:Bile Acids and Salts; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001663:Bilirubin