Hepatic peroxisome proliferation: induction by BR-931, a hypolipidemic analog of WY-14,643

Abstract

Administration of BR-931, an ethanolamine derivative of Wy-14,643 [4-chloro-6-(2,3-xylidino)-2-pyrimidinythio]acetic acid, at a dietary concentration of 0.125% for 3 weeks to male F-344 rats, resulted in a significant enlargement of the liver. The hepatomegaly appeared to be due to liver cell hyperplasia and hypertrophy resulting, in part, from peroxisome and smooth endoplasmic reticulum proliferation. The hepatic catalase and carnitine acetyltransferase activities increased significantly in association with peroxisome proliferation. The hepatomegaly and peroxisome proliferation induced by BR-931 were comparable in degree to those resulting from feeding of an equivalent dose of Wy-14,643. All these hepatic effects were reversible when the drugs were withdrawn from the diet. Screening of new compounds for hepatic peroxisome proliferation and for increases in peroxisome-associated enzymes may prove to be an adjunct to evaluating their potency as hypolipidemic agents, in view of frequent association between hepatic peroxisome proliferation and hypolipidemia.