EXPRESSION OF MYC, FOS, AND HA-RAS IN THE LIVERS OF FURAN-TREATED F344 RATS AND B6C3F(1) MICE

Furan administered by gavage for 2 yr has been reported to induce hepa tocellular carcinomas in male and female B6C3F(1) mice and in male but not female F344 rats. Chronic exposure studies in our laboratory usin g bioassay conditions showed extensive hepatocellular toxicity and sus tained increases in regenerative cell proliferation after 1, 3, and 6 wk of treatment in male and female rats and male mice. Altered express ion of growth-control genes associated with this hyperproliferative st ate may enhance the susceptibility of these genes to mutation or may p rovide a selective growth advantage to preneoplastic cells. Quantitati ve northern blot analysis of mRNA was used to examine the expression o f the oncogenes myc, fos, and Ha-ras in the livers of animals treated with furan. In male rats, a single administration of 30 mg/kg furan pr oduced necrosis and a subsequent wave of cell proliferation 48 h after treatment and induced transient peaks in the expression of myc, fos, and Ha-ras 6-24 h after treatment. In male rat liver from our cell pro liferation studies, only a slight increase in myc expression was seen at the end of week 1 of treatment. However, beginning at week 3 and in creasing at week 6, up to a 15-fold increase over control values was o bserved in the expression of myc in the treated animals. The only othe r notable increase in expression observed in any animals from the cell proliferation study was a threefold increase in myc at week 6 in trea ted female rats. The absence of an increase in Ha-ras expression in th e male mouse liver suggests that the unique pattern of Ha-ras mutation s previously reported in furan-induced mouse liver tumors is not due t o increased mutational susceptibility related to overexpression of thi s gene. The lack of sustained expression of myc, fos, and Ha-ras in ra pidly proliferating liver suggests that continuous expression of these genes is not necessary to maintain increased rates of cell replicatio n. The large increase in myc expression in male but not female rats su ggests an adaptive change that may be related to the sex-specific inci dence of furan-induced hepatocellular carcinomas in rats. (C) 1994 Wil ey-Liss, Inc.