Development of hepatocellular carcinomas and increased peroxisomal fatty acid beta-oxidation in rats fed [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio] acetic acid (Wy-14,643) in the semipurified diet.

To eliminate interference by contaminating xenobiotics that may possibly be present in the commercial rodent chow, we used semipurified diet in these studied to establish the carcinogenicity of hepatic peroxisome proliferator [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio] acetic acid (Wy-14,643). This compound was fed to male F344 rats in the semipurified diet at a dietary concentration of 0.2% (w/w) for 65 weeks. Between 40 and 65 weeks, 14 of 14 rats fed Wy-14,643 developed hepatocellular carcinomas. Therefore, the possibility that peroxisome proliferators increase the liver tumor incidence by as promoting effect appears highly unlikely, even though these compounds appear to be non-genotoxic. The liver tumors, as well as non-tumor portions of liver in Wy-14,643 fed rats, showed increased levels of peroxisomal fatty acid beta-oxidation system and H2O2. Excessive accumulation of autofluorescent lipofuscin, indicative of increased lipid peroxidation, was also observed in the liver parenchymal cells, during Wy-14,643 induced liver tumorigenesis. These observations support the contention that sustained proliferation of peroxisomes leads to oxygen radical toxicity, which may eventually lead to the development of liver tumors in rodents exposed to peroxisome proliferators.