title: Inhibition of cytochrome P-450-dependent mixed function oxidation by ethanol.
abstract: The mechanism of inhibition of cytochrome P-450-dependent mixed function oxidation by ethanol was studied. Ethanol competitively inhibited the binding of hexobarbital to liver microsomes, and increased the low spin signal of cytochrome P-450 in the electron spin resonance spectra. Therefore, ethanol decreased the substrates bound to ferric cytochrome P-450 in the first step of mixed function oxidation. The second step of mixed function oxidation is the reduction of ferric cytochrome P-450-substrate complex by NADPH-cytochrome P-450 reductase. The NADPH-dependent reduction of liver microsomal cytochrome P-450 was biphasic and composed of two first-order reactions. Ethanol decreased the rate constants of the fast and slow phases of microsomal cytochrome P-450 reduction. Thus, it is concluded that the inhibition of drug oxidation by ethanol may be due to the displacement of substrates from cytochrome P-450 and to the inhibition of reduction of cytochrome P-450 by NADPH-cytochrome P-450 reductase.
authors.forename: N
authors.initials: N
authors.lastname: Hayashi
authors.forename: T
authors.initials: T
authors.lastname: Kamada
authors.forename: N
authors.initials: N
authors.lastname: Sato
authors.forename: A
authors.initials: A
authors.lastname: Kasahara
authors.forename: J A
authors.initials: JA
authors.lastname: Peterson
mesh_terms: D015660:7-Alkoxycoumarin O-Dealkylase; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004578:Electron Spin Resonance Spectroscopy; D000431:Ethanol / Q000494:pharmacology*; D006591:Hexobarbital / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D009249:NADP / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D010084:Oxidation-Reduction; D010105:Oxygenases / Q000037:antagonists & inhibitors; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D000431:Ethanol; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D006591:Hexobarbital; D006899:Mixed Function Oxygenases; D010105:Oxygenases; D015660:7-Alkoxycoumarin O-Dealkylase; D009251:NADPH-Ferrihemoprotein Reductase