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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 Liver¹

Department of Pathology, The Northwestern University Medical School, Chicago, Illinois 60611 [J. K. R., M. S. R.]; The Clinical Pharmacology and Toxicology Center, The University of Kansas Medical Center, Kansas City, Kansas 66103 [D. L. A.]; and Department of Pathology, The University of California School of Medicine, San Diego, California 92037 [S. S.]

Long-term effects of Wy-14,643 ([4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid), a potent hepatic peroxisome proliferator structurally unrelated to the clinically used drug clofibrate, were investigated in male acatalasemic 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 acatalasemic 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 -fetoprotein 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.

¹ Supported by NIH Research Grant GM-23750.

² To whom requests for reprints should be addressed, at Department of Pathology, The Medical School, Ward Memorial Building, Northwestern University, 303 East Chicago Avenue, Chicago, Ill. 60611.

³ Present address: G. D. Searle & Co., P. O. Box 5110, Chicago, Ill. 60680.

Received 8/ 4/78. Accepted 10/ 6/78.

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