Susceptibility of germ-free rats to the hepatotoxic effects of dimethylnitrosamine or dimethylamine plus sodium nitrite administered orally.

The influence of intestinal microflora on the hepatotoxic effects of dimethylnitrosamine (DMN) or dimethylamine (DMA) plus NaNO2 was studied by comparing the degree of liver necrosis and the levels of serum alanine aminotransferase (GPT) and aspartate aminotransferase (GOT) in germ-free and conventional male Wistar rats (320 to 340 g). In one experiment, both germ-free and conventional rats were intubated with DMN in respective doses of 8, 9, and 10 mg/kg of body weight, while in another experiment, both groups were intubated with DMA (1500 mg/kg) plus NaNO2 (100 mg/kg). In both experiments, 48 hr after intubation, there was a marked difference in the degree of liver necrosis and the levels of serum GPT and GOT between the groups. In particular, a dose of 8 mg of DMN or 1500 mg of DMA plus 100 mg of NaNO2 produced severe liver necrosis in the majority of germ-free rats, while the same dose did not produce any detectable liver necrosis in the majority of conventional rats. At a dose of 8 mg, serum GPT and GOT levels were raised to 22 and 15 times normal values, respectively, in germ-free rats, but only to about twice the normal values for both levels in conventional rats. At the combination dose of DMA plus NaNO2, the levels of serum GPT and GOT were raised to 40 and 30 times normal values, respectively, in germ-free rats, while both levels remained almost normal in conventional rats. Thus, the results indicated that the liver of the germ-free state was far more susceptible to the acute toxic effects of DMN as well as DMA plus NaNO2 administration at a certain dose range than was the liver of the conventional state, suggesting the influence of the absence of microflora.