Hydrocarbon formation in the reductive cleavage of hydroperoxides by cytochrome P-450.

Evidence is presented that cytochrome P-450 catalyzes the reductive cleavage of hydroperoxides. For example, in a reconstituted system containing rabbit liver microsomal P-450 form 2, NADPH-cytochrome P-450 reductase, and NADPH, cumyl hydroperoxide yields acetophenone and methane, but no cumyl alcohol is formed. The stoichiometry of the reaction and similar results with alpha-methylbenzyl, benzyl, and t-butyl hydroperoxides are in accord with the following general equation, in which X represents an alkyl group and R and R' are either alkyl groups or hydrogen atoms in the starting peroxide: XRR'C-OOH + NADPH + H+----XRCO + R'H + H2O + NADP+. Because 13-hydroperoxy-9,11-octadecadienoic acid yields pentane under these conditions, we propose that the known formation of alkanes and aldehydes in membrane lipid peroxidation involves reductive cleavage by P-450 to give the products predicted by the above equation. The cleavage reaction is thought to involve stepwise one-electron transfer, resulting in homolysis of the peroxide oxygen-oxygen bond and generation of an alkoxy radical, with beta-scission of the latter followed by reduction of the secondary radical to the hydrocarbon. In accordance with this scheme, when the cleavage reaction with cumyl hydroperoxide was done in 2H2O, deuteromethane was formed.