Decreased hepatocyte growth factor level by Wy-14,643, non-genotoxic hepatocarcinogen in F-344 rats.

We examined the role of hepatocyte growth factor (HGF) in the hepatocarcinogenesis caused by [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio] acetic acid (Wy-14,643), a peroxisome proliferator. Wy-14,643 (100 mg/kg body wt or 0.1% (w/w) in diet) was given orally to male F-344 rats for up to 78 weeks. At 78 weeks the hepatocarcinomas or adenomas in the livers of Wy-14,643-treated rats were observed. Markedly decreased amounts of hepatic HGF mRNA were observed in rats fed Wy-14,643 for 78 weeks. The degree of reduction was higher in the tumour portions of the liver than in the normal portions. After 7 days of treatment with Wy-14,643 (100 mg/kg body wt), the expression of hepatic HGF mRNA was slightly decreased. Wy-14,643 treatment resulted in a time-dependent decrease in hepatic HGF mRNA levels to 63% of the control level after 14 days of treatment. In long-term treatment (18-40 weeks), hepatic HGF mRNA levels were reduced further, reaching 44% of the control level at the 40-week stage. As shown by ELISA, the amounts of hepatic and plasma HGF were significantly decreased by 60 and 50%, respectively, compared with controls. The degree of the reduction correlated with the level of hepatic HGF mRNA. In the lung and kidney, also HGF secretory organs, Wy-14,643 slightly reduced the amount of HGF mRNA. In the colony assay using preneoplastic or neoplastic cells from Wy-14,643-treated livers, 5-15 ng/ml of HGF, which induces proliferation in normal hepatocytes, inhibited the colony formation of neoplastic or preneoplastic cells. The inhibitory effect was dependent on HGF concentration. In the presence of 300 ng/ml HGF, the growth of colonies was suppressed to 36% of the control level. These findings indicate that reductions in hepatic HGF levels, induced by Wy-14,643, may play an important role in the promotion of neoplastic or preneoplastic cell growth.