EFFECTS OF RETINOID TREATMENT OF RATS ON HEPATIC-MICROSOMAL METABOLISM AND CYTOCHROMES P450 - CORRELATION BETWEEN RETINOIC ACID RECEPTOR RETINOID-X-RECEPTOR SELECTIVITY AND EFFECTS ON METABOLIC ENZYMES

Retinoids are compounds that bind to and activate one or more retinoid receptors to elicit various physiological responses. There are two fa milies of retinoid receptors, i.e. retinoic acid receptors (RAR) and r etinoid X receptors (RXR), for which the various synthetic and natural ly occurring retinoids have differing selectivities. The synthetic ana logs LG100268 and LGD1069 (Targretin) are RXR-selective, whereas ALRT1 550 is highly RAR-selective. Naturally occurring all-trans-retinoic ac id (Tretinoin) has a degree of selectivity for RAR, whereas ALRT1057 ( 9-cis-retinoic acid, Panretin) is equally active at RAR and RXR (i.e. a pan-agonist). To evaluate the effects of these compounds on metaboli c enzymes, male Sprague-Dawley rats received daily oral doses for 4 da ys, and liver microsomes were prepared on day 5. As a class, these lig ands exerted profound effects on hepatic microsomal metabolic enzyme l evels. Those with RAR activity decreased hepatic cytochrome P450 (CYP or P450) levels and in vitro metabolism of the compound of pretreatmen t, whereas those exerting predominantly RXR activity increased these p arameters. A similar relationship was observed when glucuronidation wa s examined. Hepatic CYP2B1/2 was unaffected and CYP3A was decreased by RAR-selective ALRT1550, whereas both were induced by ligands selectiv e for RXR. However, both RAR- and RXR-selective ligands decreased CYP1 A2, whereas they induced CYP4A. Although the mechanisms underlying the se effects are not known, these results suggest that RAR- and RXR-bind ing ligands exert distinct effects on hepatic metabolism, and they ind icate the potential for drug-drug interactions, especially involving C YP3A. The nature of such interactions would depend on the RAR/RXR sele ctivity of the ligand and the P450 isozymes responsible for the metabo lism of coadministered drugs.