Rapid hepatoma induction in rats by dipentylnitrosamine and its modification by other carcinogens

Dipentylnitrosamine (DPN), administered in the diet at a concentration of 2,000 ppm to Fischer-344 rats, produced hepatomas in 27% of both males and females within 8 weeks. Bile-duct carcinomas were also produced. All animals also showed liver nodular hyperplasia and bile-duct cell proliferation. Feeding DPN at 1,500 ppm produced hepatomas or bile-duct carcinomas in 7% of the males and varying degrees of nodular hyperplasia and duct cell proliferation after 8 weeks of feeding. The total cumulative dose after feeding 2,000 ppm DPN was of the order of 7,700 mg/kg body weight in males and 8,200 mg/kg in females. There was a 28% weight decrement in animals feed 2,000 ppm DPN when compared to controls but no mortality. DPN carcinogenicity was enhanced when DPN was combined with a liver carcinogen, cycasin (fed as cycad not flour, equivalent to 160 ppm cycasin). No effect on DPN carcinogenicity was found in rats fed DPN and lasiocarpine, another known liver carcinogen with antimitotic activity. Neither was there any effect of DPN carcinogenicity in rats fed DPN and N-butyl-N-(4-hydroxybutyl) nitrosamine or N-methyl-N'-nitro-N-nitrosoguanidine. In contrast, the trisodium salt of nitrilotriacetic acid reduced the hepatocarcinogenic action of DPN. The enhancement of DPN carcinogenicity with cycasin is compatible with the hypothesis that DPN-induced liver cell populations (hyperplastic nodules) can resist the cytotoxic effect of cycasin and differentiate rapidly towards hepatomas, while other areas of the liver are suppressed.