Electron transfer in P450 mechanisms. Microsomal metabolism of cyclopropylbenzene and p-cyclopropylanisole.
1. The metabolism of cyclopropylbenzene (1a) and 4-cyclopropylanisole (1b) was studied using liver microsomal preparations from control, phenobarbital- and beta-naphthoflavone treated rats. 2. With all three types of microsomes 1a was metabolized by benzylic hydroxylation to give 1-phenylcyclopropanol and by aromatic hydroxylation at C-4; the former predominated by a factor of 2-4. BNF-induced microsomes also formed 2-cyclopropylphenol. No cyclopropyl ring-opened metabolites of 1a, including benzoic acid, were detected in any of the incubations. 3. With PB-induced microsomes 1b underwent O-demethylation (90%) and benzylic hydroxylation; no other metabolites were detected. 4. Progress curves for metabolism of 1a are markedly nonlinear after only limited conversion of substrate, suggesting the possibility that 1a, like other cyclopropyl compounds, could be a suicide substrate for one or more isozymes of P450. 5. For both 1a and b, metabolite formation and enzyme inactivation can be explained by conventional P450 reaction mechanisms not involving electron abstraction.
Riley
P
P
Department of Medicinal Chemistry, University of Kansas, Lawrence 66045-2506.
Hanzlik
R P
RP
D000818:Animals; D000840:Anisoles / Q000378:metabolism*; D001555:Benzene Derivatives / Q000378:metabolism*; D001565:Benzoates / Q000378:metabolism; D019817:Benzoic Acid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004579:Electron Transport; D004790:Enzyme Induction; D006900:Hydroxylation; D007527:Isoenzymes / Q000378:metabolism*; D007700:Kinetics; D008745:Methylation; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D010084:Oxidation-Reduction; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats
D000840:Anisoles; D001555:Benzene Derivatives; D001565:Benzoates; D007527:Isoenzymes; C086834:4-cyclopropylanisole; C036181:cyclopropylbenzene; D019817:Benzoic Acid; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital