title: 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.
abstract: Retinoids are compounds that bind to and activate one or more retinoid receptors to elicit various physiological responses. There are two families of retinoid receptors, i.e. retinoic acid receptors (RAR) and retinoid X receptors (RXR), for which the various synthetic and naturally occurring retinoids have differing selectivities. The synthetic analogs LG100268 and LGD1069 (Targretin) are RXR-selective, whereas ALRT1550 is highly RAR-selective. Naturally occurring all-trans-retinoic acid (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 metabolic enzymes, male Sprague-Dawley rats received daily oral doses for 4 days, and liver microsomes were prepared on day 5. As a class, these ligands exerted profound effects on hepatic microsomal metabolic enzyme levels. Those with RAR activity decreased hepatic cytochrome P450 (CYP or P450) levels and in vitro metabolism of the compound of pretreatment, whereas those exerting predominantly RXR activity increased these parameters. A similar relationship was observed when glucuronidation was examined. Hepatic CYP2B1/2 was unaffected and CYP3A was decreased by RAR-selective ALRT1550, whereas both were induced by ligands selective for RXR. However, both RAR- and RXR-selective ligands decreased CYP1A2, whereas they induced CYP4A. Although the mechanisms underlying these effects are not known, these results suggest that RAR- and RXR-binding ligands exert distinct effects on hepatic metabolism, and they indicate the potential for drug-drug interactions, especially involving CYP3A. The nature of such interactions would depend on the RAR/RXR selectivity of the ligand and the P450 isozymes responsible for the metabolism of coadministered drugs.
authors.affiliation: Department of Drug Safety and Disposition, Ligand Pharmaceuticals, Inc., San Diego, CA 92121, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Howell
authors.forename: M A
authors.initials: MA
authors.lastname: Shirley
authors.forename: E H
authors.initials: EH
authors.lastname: Ulm
mesh_terms: D000818:Animals; D000077610:Bexarotene; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000502:physiology*; D007527:Isoenzymes / Q000032:analysis / Q000502:physiology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D015394:Molecular Structure; D009539:Nicotinic Acids / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000378:metabolism; D047488:Retinoid X Receptors; D012176:Retinoids / Q000494:pharmacology*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D007527:Isoenzymes; D009539:Nicotinic Acids; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012176:Retinoids; D013764:Tetrahydronaphthalenes; D014157:Transcription Factors; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D000077610:Bexarotene; C095104:LG 100268