28] Reductive cleavage of hydroperoxides by cytochrome P-450

Abstract

This chapter describes the reductive cleavage of hydroperoxides by cytochrome P- 450. Various forms of liver microsomal cytochrome P-450 (cytochrome P- 450 LM ) are known to catalyze numerous chemical reactions, including the hydroxylation of fatty acids, steroids, and a variety of foreign compounds, such as drugs and carcinogens. These monooxygenation reactions require aerobic conditions and nicotine adenine dinucleotide phosphate hydrogenase (NADPH) as the electron donor in microsomal suspensions or in the reconstituted system containing purified cytochrome P-450 LM , purified NADPH-cytochrome-P-450 reductase, and phosphatidylcholine. On the other hand, molecular oxygen, NADPH, and the reductase are not required when organic hydroperoxides or related compounds serve as the oxygen donor in cytochrome P-450 LM -catalyzed substrate hydroxylations. In such reactions, the hydroperoxides are converted to the corresponding alcohols so that cumyl hydroperoxide, for example, is converted to cumyl alcohol. Other model hydroperoxides in addition to cumyl serve as substrates in the reductive cleavage reaction. α-Methylbenzyl hydroperoxide yields acetophenone as well as benzaldehyde because either a hydrogen atom or a methyl group can be lost, benzyl hydroperoxide yields benzaldehyde, and tert -butyl hydroperoxide yields acetone and methane. With limiting amounts of cytochrome P-450 form present, the turnover numbers, expressed as nanomoles of NADPH oxidized per minute per nanomole of the cytochrome, are 60, 30, 24, and 6 for tert -butyl, cumyl, α-methylbenzyl, and benzyl hydroperoxides, respectively. Pentane has been identified as a cleavage product of the 15-hydroperoxide derived from arachidonic acid as well as from the 13-hydroperoxide derived from linoleic acid.