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 isoforms.
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.
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
J F
JF
Muindi
C W
CW
Young
D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D008054:Lipid Peroxides / Q000378:metabolism*; D008861:Microsomes / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D018168:Receptors, Retinoic Acid; D014212:Tretinoin / Q000378:metabolism*
D002352:Carrier Proteins; D007527:Isoenzymes; D008054:Lipid Peroxides; D018168:Receptors, Retinoic Acid; D009249:NADP; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System