Mitogenic and Carcinogenic Effects of a HypolipidemicPeroxisome Proliferator, (4-Chloro-6-(2,3-xylidino)-2-pyrimidinylthiojacetic Acid (Wy-14,643), in Rat and Mouse Liver1

pidemic drug clofibrate (ethyl-a-p-chlorophenoxyisobutyr ate) in lowering serum lipid levels in experimental animals (49) but it did not enter into clinical trials, possibly due to suspected hepatotoxicity in experimental animals. Previous work by Reddy and Knishnakantha (31) showed that Wy 14,643 caused a significant hepatomegaly and produced a marked increase in the hepatic peroxisome population in rats and mice. Subsequently, we have demonstrated that structurally related analogs of Wy-14,643 that lacked hypo lipidemic effect failed to induce hepatic penoxisome prolif eration and peroxisome-associated enzymes (28, 34). During the past 5 years, several chemicals with a hypoli pidemic property have been identified as hepatic peroxi some (micnobody) proliferators in rats and mice (29, 31, 33). Because of this association, a relationship between hepatic peroxisome proliferation and lipid metabolism was sug gested (31). Recently, Lazarow and DeDuve (18) and Laza now (17) presented evidence to indicate that peroxisomes catalyze the /3-oxidation of long-chain fatty acids. The presence in peroxisomes of a fatty acyl-CoA-oxidizing sys tem (17, 18) and carnitine acetyltnansferase (20) and their increase in the livers of animals treated with peroxisome proliferators(11, 12, 18, 22, 23, 26, 48) appear to substanti ate the relationship between penoxisome proliferation and lipid metabolism. Because of the long-term administration of drugs such as clofibrate for the control of hypenlipidemic states in man (7), it is essential to investigate various aspects of the persistent hepatomegaly and penoxisome proliferation in duced by these agents. Long-term feeding of nafenopin (2methyl-2-[p-(1 ,2,3,4-tetrahydno-i -naphthyl)phenoxyjpnopi onic acid; Su-13,437), a closely related analog of clofibrate, has been shown to induce hepatocellular carcinomas in rats and acatalasemic mice (35, 38). The availability of several compounds with diverse chemical structures that induce peroxisome proliferation in liver cells (29, 31 , 33, 47) provides an opportunity to investigate the relationship, if any, between peroxisome proliferation, hepatomegaly, and hepatocarcinogenesis. We now report that Wy-14,643 (Chart 1), a potent hypolipidemic penoxisome proliferator, which is structurally different from clofibrate, is a mitogen , forliverandinduceshepatocellular carcinomas inratsand mice.