Retinal dehydrogenation and retinoic acid 4-hydroxylation in rat hepatic microsomes: developmental studies and effect of foreign compounds on the activities.
All-trans-retinoic acid (RA) regulates the transcription of a number of mammalian genes and is therefore important in the control of many cellular processes. RA is formed and deactivated within the cell so that biotransformation modulates RA availability. This study investigate the relationship between the formation of RA from retinal and its metabolism by 4-hydroxylation in rat hepatic microsomes. From kinetic studies the Michaelis constants for RA formation and 4-hydroxylation were 52 and 24 microM, respectively, and the maximal reaction velocities were 33 and 136 pmol/min/mg protein, respectively. Thus, 4-hydroxylation was the more efficient process. In microsomes from 1-week-old rats, RA formation was very low (approximately 2 pmol/min/mg protein) but was several-fold greater in adults of both sexes (approximately 10 pmol/min/mg protein). In contrast, 4-hydroxylation was quantitatively more significant at all ages examined between 1 and 15 weeks; by 10 and 15 weeks a sexual dimorphism was apparent (M > F). Thus, the ratio of RA 4-hydroxylation to RA formation was comparatively large in microsomes from 1-week-old rats and declined to a stable value around 4-6 weeks of age. With the exception of dexamethasone, which decreased the activity, administration of foreign compounds to male rats had little effect on RA formation. Both dexamethasone and phenobarbital induced RA 4-hydroxylation but DMSO and beta-naphthoflavone were without effect. From these findings, 4-hydroxylation, particularly in very young animals, may be an effective means of controlling RA production. RA 4-hydroxylation, like other cytochrome P450 activities, was inducible in rat liver but no evidence was found for induction of the microsomal retinal dehydrogenase.
Martini
R
R
Department of Medicine, University of Sydney, Westmead Hospital, NSW, Australia.
Murray
M
M
D000375:Aging / Q000378:metabolism; D000445:Aldehyde Oxidoreductases; D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D005260:Female; D006865:Hydrogenation; D006900:Hydroxylation; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D050697:Retinal Dehydrogenase; D012172:Retinaldehyde / Q000378:metabolism*; D014212:Tretinoin / Q000378:metabolism*; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D014212:Tretinoin; D019324:beta-Naphthoflavone; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D000445:Aldehyde Oxidoreductases; D050697:Retinal Dehydrogenase; D012172:Retinaldehyde; D004121:Dimethyl Sulfoxide; D010634:Phenobarbital