Role of cytochrome P-450 in the metabolism of lipid hydroperoxides, retinoids, and xenobiotic aldehydes.

Abstract

The role of rabbit liver microsomal cytochrome P-450, a versatile biological catalyst, has been investigated in the metabolism of xenobiotic and lipid hydroperoxides, retinoids, and aldehydes. As shown previously in this laboratory, purified P-450 2B4 catalyzes the reductive cleavage of xenobiotic hydroperoxides to yield hydrocarbons and aldehydes or ketones. The present research has demonstrated that the alcohol-inducible P-450 2E1 is the most active isozyme with lipid as well as xenobiotic hydroperoxides. The occurrence of this reaction was also demonstrated in liver microsomal membranes. Products from the reaction with cumyl hydroperoxide in the presence of microsomal membranes include the reductive cleavage product, acetophenone, as well as cumyl alcohol, 1-phenylethanol, and $\alpha$-hydroxyacetophenone. In addition, the metabolism of retinoic acid, retinol, and retinal has been investigated with purified isozymes of P-450. Retinoids hydroxylated at the 4 position were found to be major metabolites with each of the isozymes examined. Only two of the isozymes, P-450s 1A2 and 3A6, also catalyze the oxidation of retinal to retinoic acid, a reaction not previously attributed to P-450. Finally, the P-450-dependent oxidative cleavage of cyclohexane carboxaldehyde to yield formic acid and cyclohexene in a reaction believed to involve a peroxyhemiacetal-like adduct, formed between the substrate and molecular oxygen-derived hydrogen peroxide, is described. The reaction is a useful model for the demethylation reactions catalyzed by the steroidogenic P-450s, aromatase and lanosterol demethylase. Aldehydes with branching at the $\alpha$ or $\beta$ carbon, including citronellal, a $\beta$-branched aldehyde found in many essential oils, are converted to the predicted olefinic products while straight chain aldehydes are not. The activity of various P-450 isoforms was found to increase with increased branching at the $\alpha$ carbon. The oxidative cleavage reaction with olefin formation appears to be widespread, as judged by the variety of aldehydes that serve as substrates and of P-450 cytochromes that serve as catalysts. The results reported herein support the idea that P-450 isozymes play a role in the metabolism of physiological compounds such as lipid hydroperoxides and retinoids, in addition to xenobiotics, and that their metabolism may be affected by exposure of the animal to various inducing agents of P-450.