Hepatocarcinogenesis by peroxisome proliferators.

It is well known that various kinds of hypolipidemic drugs induce marked changes in the livers of rats and mice. The initial hepatic responses in rodents are marked hepatomegaly, proliferation of peroxisomes in association with changes in peroxisome structure and enzyme composition. Furthermore, since many of hypolipidemic peroxisome proliferators induce hepatocellular carcinomas in both rats and mice, the relationship between peroxisome proliferation and hepatocarcinogenicity of these drugs has become extremely important. However, it has not yet been established whether there are any direct relationships among pharmacological action, peroxisome proliferation and carcinogenicity of these drugs. In order to clarify this task, we have studied the involvement of HGF in hepatocarcinogenesis caused by peroxisome proliferators. After male F-344 rats were orally given Wy-14,643, hepatocarcinomas and (pre) neoplastic nodules were observed in the livers. At that time, the content of HGF and the expression of HGF mRNA were significantly decreased in the liver tumors. These findings may indicate that decreases in hepatic HGF levels are specific events induced by peroxisome proliferators but not by genotoxic carcinogenesis, and that those changes play an important role in the promotion of neoplastic or preneoplastic cell growth induced by peroxisome proliferators. Decrease in HGF induced by peroxisome proliferators such as Wy-14,643 would inhibit the growth of normal hepatocytes and then lend an advantageous circumstance for the selective growth of neoplastic or preneoplastic cells, resulting in the development of growth of tumors.