Dietary glucarate-mediated inhibition of initiation of diethylnitrosamine-induced hepatocarcinogenesis.

Previously, it has been reported that calcium glucarate is a potent inhibitor of chemical carcinogenesis, including phenobarbital-promoted diethylnitrosamine-initiated hepatic toxicity expressed as altered hepatic foci in rats. The purpose of the present study was to determine whether calcium glucarate could inhibit the immediate and delayed appearance of altered hepatic foci when fed to rats during the initiation phase of diethylnitrosamine-induced hepatocarcinogenesis. The effects of dietary mode of administration of calcium glucarate on the initiation phase of hepatocarcinogenesis were also examined. Since diethylnitrosamine is not known to undergo glucuronidation and calcium glucarate has been shown to enhance clearance of circulating estrogens, an indirect mechanism of action of calcium glucarate was also evaluated by pretreating rats with an anti-estrogen, tamoxifen, prior to partial hepatectomy and administration of diethylnitrosamine. Calcium glucarate significantly inhibited both the early and delayed appearance of altered hepatic foci and exerted maximal inhibition when administered by gavage prior to diethylnitrosamine. Maximal inhibition was obtained when calcium glucarate was provided continuously in the diet of animals up to 5 and 7 months. Pretreatment of animals with tamoxifen before partial hepatectomy and diethylnitrosamine resulted in maximal inhibition of the initiation phase of hepatocarcinogenesis. This suggests but does not prove that the anti-carcinogenic activity of calcium glucarate was due to decreased liver proliferation. In the present study, the proliferation of ductular epithelial and oval cells appeared to be associated with the administration of diethylnitrosamine. Collectively, our data suggest that calcium glucarate inhibited the initiation phase of diethylnitrosamine-induced hepatocarcinogenesis.