EVIDENCE THAT THE HEPATOTOXICITY OF N-NITROSODIMETHYLAMINE IN THE RATIS UNRELATED TO DNA METHYLATION

N-Nitrosodimethylamine (NDMA) is a potent hepatotoxicant in the rat, b ut the mechanism by which it lethally injures hepatocytes is not known . NDMA is metabolized in the liver to the methanediazonium ion that me thylates hepatic DNA. Neither N-nitrosomethylbenzylamine (NMBzA) nor m ethylnitrosourea (MNU) produces liver tumors, but via metabolism in th e case of NMBzA, or via spontaneous decomposition at physiological pH in the case of MNU, both compounds produce the methanediazonium ion an d methylate hepatic DNA. Here we have compared quantitatively the abil ity of NDMA, NMBzA, and MNU to cause lethal injury to hepatocytes in v ivo and to produce O6-methylguanine in hepatic DNA. Neither NMBzA nor MNU produced hepatotoxicity in the rat even at doses as high as 667 mu mol/kg body wt for NMBzA and 971 mumol/kg body wt for MNU. NMBzA given at the same time as NDMA potentiated the hepatotoxicity of NDMA, but O6-methylguanine levels were only additive. MNU did not potentiate the hepatotoxicity of NDMA, but again, the 06-methylguanine levels were a dditive when NDMA and MNU were administered together. These results ap pear to rule out the involvement of DNA methylation in lethal hepatocy te injury by NDMA.