title: Fate of free radicals generated during one-electron reductions of 4-alkyl-1,4-peroxyquinols by cytochrome P-450.
abstract: Free radicals resulting from the one-electron reduction and subsequent homolytic cleavage of oxygen-oxygen bonds by heme proteins are likely to be responsible for some aspects of the toxicity of organic hydroperoxides. In the present work, effects of the 4-alkyl substituent of 2,6-di-tert-butyl-4-alkyl-4-hydroperoxycytohexa-2,5-dienones (1,4-peroxyquinols) on radical production were investigated with microsomal cytochrome P-450 from rat liver. Quinoxy radicals from homolysis of the peroxyquinols underwent beta-scission to produce a quinone and an alkyl radical, and this process occurred with increasing frequency as the stability of the alkyl radical increased. The fate of benzyl and 2-phenylethyl radicals generated from the appropriately substituted peroxyquinols was investigated also. The former was converted to benzyl alcohol, benzaldehyde, and toluene and the latter to 2-phenylethanol, phenylacetaldehyde, ethylbenzene, styrene, and benzaldehyde. Oxygen-18 labeling studies demonstrated that 80-85% of the benzyl alcohol incorporated oxygen from the hydroperoxide and the balance from molecular oxygen. This indicates that the predominant reaction pathway involved recombination between the benzyl radical and the iron-bound hydroxyl radical of the P-450 intermediate complex. By contrast, about 50% of 2-phenylethanol from the 2-phenylethyl radical incorporated oxygen from water and the balance from O2. Two alternative mechanisms are proposed to explain the formation of 2-phenylethanol that contained oxygen from water and the concurrent formation of styrene: (a) oxygen exchange of the P-450 intermediate with water, followed by hydrogen abstraction and radical recombination reactions with the P-450 complex, or (b) oxidation of the radical to the 2-phenylethyl cation followed by proton elimination and hydration.
authors.affiliation: Molecular and Environmental Toxicology Program, School of Pharmacy, University of Colorado, Boulder 80309-0297.
authors.forename: N P
authors.initials: NP
authors.lastname: Yumibe
authors.forename: J A
authors.initials: JA
authors.lastname: Thompson
mesh_terms: D000478:Alkylation; D000818:Animals; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005609:Free Radicals; D008401:Gas Chromatography-Mass Spectrometry; D006873:Hydroquinones / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D010084:Oxidation-Reduction; D010545:Peroxides / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013379:Substrate Specificity
chemical_list: D005609:Free Radicals; D006873:Hydroquinones; D010545:Peroxides; D003577:Cytochrome P-450 Enzyme System