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Lipid Hydroperoxides Greatly Increase the Rate of Oxidative Catabolism of All-trans-Retinoic Acid by Human Cell Culture Microsomes Genetically Enriched in Specified Cytochrome P-450 Isoforms¹

Clinical Pharmacology Laboratory and the Developmental Chemotherapy Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Cytochrome P-450 enzymes have been implicated in the oxidative catabolism of all-trans-retinoic acid (RA), a process that is accelerated by exposure to RA in cultured cells and rodents, and also in patients receiving RA as treatment for cancer (J. F. R. Muindi et al., Cancer Res., 52: 2138, 1992; Blood, 79: 299, 1992). Accelerated oxidation of RA could arise from an induction of RA-catabolizing P-450 isoforms or from an increase in oxidative cofactors. We have examined the efficiency of NADPH/O₂ and lipid hydroperoxides (LOOH) to support oxidation of RA using human cell microsomes genetically enriched in different P-450 isoforms. The observed rate of RA oxidation using the NADPH/O₂ system was slow for all isoforms (6–23 pmol/mg protein/min). LOOH-mediated oxidation was much faster (24–1078 pmol/mg protein/min), not isoform specific, but dependent upon the chemical nature of the LOOH. The order of efficiency of RA oxidation using LOOH was 13-hydroperoxy[S-(E,Z)]-9,11-octadecadienoic acid > 5-hydroperoxy[S-(E,Z,Z,Z)]-6,6,11,14-eicosatetraenoic acid > prostaglandin G₂ > cumene hydroperoxide > tert-butylhydroperoxide > H₂O₂. Whereas submicromolar concentrations of 13-hydroperoxy[S-(E,Z)]-9,11-octadecadienoic and 5-hydroperoxy[S-(E,Z,Z,Z)]-6,6,11,14-eicosatetraenoic acid oxidized RA at appreciable rates, micromolar concentrations were required for the other LOOH. These observations suggest that physiological LOOH, generated by the arachidonic acid-lipoxygenase system, may be involved in the self-induced oxidative catabolism of RA.

¹ Supported in part by USPHS Grants CA 05826 and CA 08748. Presented in part at the Fifth International Congress on Differentiation Therapy, Villasimius, Sardinia, Italy, September 2–5, 1992.

² To whom requests for reprints should be addressed, at Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021.

Received 12/28/92. Accepted 1/29/93.

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