RETINOID-INDUCED HYPERTRIGLYCERIDEMIA IN RATS IS MEDIATED BY RETINOICACID RECEPTORS

Retinoids in clinical use today are known to induce hypertriglyceridem ia as one of their major side effects. The purpose of the present stud was to determine, in an appropriate animal model, if retinoid-induced hypertriglyceridemia is mediated by retinoic acid receptors (RARs) an d/or by retinoid X receptors (RXRs). Oral gavage of male Fischer rats with 13-cis-retinoic acid for 6 days caused a rapid acid sustained inc rease in serum triglycerides that was reversible within 4 days posttre atment. In subsequent experiments, rats were treated by gavage once da ily for 3 days with various retinoids, and serum triglyceride levels w ere determined 24 hr after the last treatment without fasting. All-tra ns- and 13-cis-retinoic acid, which can be converted to both RAR and R XR agonists, and 9-cis-retinoic acid, an RAR/RXR pan-agonist, caused d ose-dependent increases in serum triglycerides at doses that did not c ause weight loss or mucocutaneous toxicity. Ro 13-6298 and AGN 190121, two RAR-specific agonists, caused dose-dependent increases in serum t riglycerides, although Ra 13-6298 only induced hypertriglyceridemia at weight-suppressive doses, Two RXR-selective agonists, LG100268 and AG N 191701, failed to induce hypertriglyceridemia or weight loss up to t he highest doses tested. A structural isomer of AGN 190121 that does n ot activate RARs or RXRs, AGN 190727, did not induct hypertriglyceride mia. Hypertriglyceridemia induced by AGN 190121 was significantly inhi bited by cotreatment with an RAR-selective antagonist, AGN 193109. Tak en together, these data provide strong evidence that retinoid-induced hypertriglyceridemia is mediated, at least in part, by RARs. These dat a also suggest that RXR-specific agonists may have reduced potential t o induce hypertriglyceridemia relative to RAR-active retinoids. (C) 19 96 Society of Toxicology.