INHIBITION OF MICROSOMAL 17-BETA-HYDROXYSTEROID OXIDOREDUCTION ACTIVITIES IN RAT-LIVER BY ALL-TRANS-RETINOIC, 9-CIS-RETINOIC AND 13-CIS-RETINOIC ACID

Retinoids and steroid hormones mediate their biological effects throug h nuclear receptors. However, retinoids may alter the intracellular av ailability of ligands for steroid receptor activation by modulating th e activity of biotransformation enzymes. This study investigated the m odulation of NAD(H)-linked steroid oxidoreductases in rat hepatic micr osomes by retinoids. 13-cis-Retinoic acid inhibited testosterone 17 be ta-dehydrogenation (K-i 2.4 +/- 0.5 mu M; K-m/K-i ratio 0.34 +/- 0.06) but androstenedione reduction was less susceptible to inhibition (K-i 27 +/- 13 mu M; K-m/K-i ratio 0.045 +/- 0.12). All-trans-retinoic aci d was less potent than the 15-cis-isomer and 9-cis-retinoic acid was o f intermediate potency. In vivo administration of all-trans-retinoic a cid (60 mg/kg i.p. for 7 days) decreased hepatic microsomal oxidoreduc tion activity, but exposure over shorter periods and 13-cis-retinoic a cid were without effect. Thus, all-trans-retinoic acid elicits direct inhibition and may also alter the normal regulation of the oxidoreduct ase under certain conditions. Three geometric isomers of retinal were potent inhibitors of testosterone dehydrogenation (IC(50)s similar to 6 mu M), 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.