The hepatic microsomal mixed-function oxidase system in man: cofactor effects and the influence of cholestasis.
Microsomal preparations from 22 surgical specimens of normal, cholestatic or severely diseased human liver were analyzed with respect to the amounts of cytochromes P-450 and b5 and NADPH-cytochrome c reductase present. Normal human liver contained slightly less NADPH-cytochrome c reductase and cytochrome P-450 (mean 102.6 +/- 14.6 nmol/mg of protein per min. and 0.60 +/- 0.10 nmol/mg of protein, respectively) than is found in the adult rat, but wide variations were observed. Cytochrome b5 was present in comparable amounts to that in rat liver, and cytochrome b5/P --450 ratios were slightly increased in human liver as compared with rat liver. Cholestatic liver did not show significant alterations in the specific contents of any of these three components of the microsomal mixed-function oxidase system, but the two livers with severe parenchymal disease showed substantial reductions in all three. In vitro investigations of cofacter interrelationships in the N-demethylation of ethylmorphine by human liver microsomes suggested that NADPH was the favored electron donor, but NADH had a substantial (ca. 20%) synergistic effect (which was not enhanced by cyanide addition). These observations are in keeping with cytochrome b5 having a possible role in cytochrome P-450-mediated drug hydroxylation in man in both the normal state and after onset of cholestasis.
D000328:Adult; D000368:Aged; D002779:Cholestasis / Q000201:enzymology*; D003067:Coenzymes / Q000378:metabolism*; D003486:Cyanides / Q000494:pharmacology; D003580:Cytochromes / Q000378:metabolism; D004579:Electron Transport; D005037:Ethylmorphine-N-Demethylase / Q000378:metabolism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism*
D003067:Coenzymes; D003486:Cyanides; D003580:Cytochromes; D009243:NAD; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D005037:Ethylmorphine-N-Demethylase; D009251:NADPH-Ferrihemoprotein Reductase