Inhibition of microsomal 17 beta-hydroxysteroid oxidoreduction activities in rat liver by all-trans-, 9-cis- and 13-cis-retinoic acid.
Retinoids and steroid hormones mediate their biological effects through nuclear receptors. However, retinoids may alter the intracellular availability of ligands for steroid receptor activation by modulating the activity of biotransformation enzymes. This study investigated the modulation of NAD(H)-linked steroid oxidoreductases in rat hepatic microsomes by retinoids. 13-cis-Retinoic acid inhibited testosterone 17 beta-dehydrogenation (Ki 2.4 +/- 0.5 microM; Km/Ki ratio 0.34 +/- 0.06) but androstenedione reduction was less susceptible to inhibition (Ki 27 +/- 13 microM; Km/Ki ratio 0.045 +/- 0.12). All-trans-retinoic acid was less potent than the 13-cis-isomer and 9-cis-retinoic acid was of intermediate potency. In vivo administration of all-trans-retinoic acid (60 mg/kg i.p. for 7 days) decreased hepatic microsomal oxidoreduction activity, but exposure over shorter periods and 13-cis-retinoic acid were without effect. Thus, all-trans-retinoic acid elicits direct inhibition and may also alter the normal regulation of the oxidoreductase under certain conditions. Three geometric isomers of retinal were potent inhibitors of testosterone dehydrogenation (IC50s approximately 6 microM), but were ineffective against androstenedione reduction. These findings suggest that certain anti-hormonal effects of retinoids may be attributable in part to modulation of endobiotic biotransformation prior to receptor binding and activation.
Murray
M
M
Department of Medicine, University of Sydney, Westmead Hospital, NSW, Australia.
Butler
A M
AM
Martini
R
R
D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D000735:Androstenedione / Q000378:metabolism; D000818:Animals; D005260:Female; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013739:Testosterone / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*
D013739:Testosterone; D000735:Androstenedione; D014212:Tretinoin; D015067:17-Hydroxysteroid Dehydrogenases