Mitogenic and Carcinogenic Effects of a Hypolipidemic Peroxisome Proliferator, [4-Chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic Acid (wy-14,643), in Rat and Mouse Liver

Long-term effects of Wy-14,643 ([4-chloro-6-(2,3-xyli-dino)-2-pyrimidinylthio]acetic acid), a potent hepatic peroxisome proliferator structurally unrelated to the clinically used drug clofibrate, were investigated in male acatalase-mic CS^b mice and F344 rats. Acatalasemic mice were fed Wy-14,643 at a dietary concentration of 0.1% (w/w) for 6 months and then at 0.05% (w/w) until the termination of the experiment at 14.5 months. F344 rats were fed this compound at a 0.1% (w/w) level in the diet for 16 months. Hepatocellular carcinomas developed in 18 of 18 acatala-semic mice and 15 of 15 F344 rats that survived chronic Wy-14,643 treatment. Metastases to lungs were observed in 5 of 18 mice and 6 of 15 rats with Wy-14,643-induced hepatocellular carcinomas. The primary liver tumors in rats contained numerous peroxisomes. The increase in the number of these organelles in tumor cells was associated with a significant elevation of carnitine acetyltransferase activity, suggesting that these intrahepatic tumors respond to the peroxisome proliferative effect of Wy-14,643. The catalase activity of these tumors, however, was not increased. Short-term administration of Wy-14,643 induced DNA replication and cell division in the rat liver as determined by [³H]thymidine incorporation into DNA, autoradiography, and colchicine-arrested metaphases in liver cells. The stimulation of liver cell proliferation was not associated with hepatocellular necrosis. The elevations of serum a-fetopro-tein concentration were associated with and proportional to liver cell proliferation. The observation that nafenopin and Wy-14,643, 2 structurally unrelated hypolipidemic agents, induce “primary” liver cell proliferation and hepatocellular carcinomas prompts a concern over the potential carcinogenicity of hepatic peroxisome proliferators as a class.