Mitogenic effect of retinoid X receptor agonists in rat liver

(E)-2-[2-(5,6,7,8-Tetrahydro-3,5,5,8,8-pentamethyl-2-naphthyl) propen-1-yl]-4-thiophenecarboxylic acid (AGN 191701) and other retinoid X receptor (RXR)-selective agonists were observed to cause hepatomegaly in rats. The purpose of the present study was to understand the biochemical basis of RXR agonist-induced hepatomegaly. Male Fischer rats were implanted s.c. with osmotic pumps containing 5-bromo-2'-deoxyuridine (BrdU) and treated by gavage with 0,60, or 180 mumol/kg/day of AGN 191701 for 3 days. AGN 191701 caused dose-dependent hepatomegaly in the absence of hepatic necrosis and necrosis and increased hepatocyte BrdU labeling index (LI). To determine if AGN 191701-induced hepatic hyperplasia was sustained, rats were treated by gavage with 60 mumol/kg of AGN 191701 for up to 7 days and exposed to BrdU via osmotic pump on days 1-3 or on days 6-8. Hepatocyte L1 and mitotic index were increased only in rats exposed to BrdU on days 1-3, indicating that AGN 191701-induced hepatocyte proliferation was transient. The receptor specificity of this mitogenic effect was tested by co-treating rats for 2 days with various retinoids and BrdU. 2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-(4-carboxylph enyl)-1,3-dioxolane (SR11237), an RXR-selective agonist, and (E)-5-[2-(5,6,7,8-tetrahydro-3,5,5,8-pentamethyl-2-naphthyl)propen -1-yl]-2-thiophenecarboxylic acid (AGN 191659), a retinoic acid receptor (RAR)/RXR pan-agonist, both increased hepatocyte LI. Two RAR-selective agonist, all-trans-retinoic acid and (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propen -1-yl] benzoic acid (TTNPB), did not affect hepatocyte LI. To determine if RXR agonists have biochemical effects in common with a peroxisome proliferator, various endpoints were measured 24 hr after two daily treatments with AGN 191701, SR11237, or clofibrate. While all three compounds induced hepatic acyl CoA oxidase activity, only clofibrate increased hepatic carnitine acyl transferase activity and lowered serum triglycerides. Taken together, these data show that RXR-selective agonists but not RAR-selective agonists cause hepatomegaly accompanied by hepatocyte mitogenesis in rats. The fact that RXR agonist have some biological effects distinct from RAR agonists and clofibrate suggests that RXR-selective agonists may have unique therapeutic applications.