Evidence that the hepatotoxicity of N-nitrosodimethylamine in the rat is unrelated to DNA methylation

N-Nitrosodimethylamine (NDMA) is a potent hepatotoxicant in the rat, but the mechanism by which it lethally injures hepatocytes is not known. NDMA is metabolized in the liver to the methanediazonium ion that methylates hepatic DNA. Neither N-nitrosomethylbenzylamine (NMBzA) nor methylnitrosourea (MNU) produces liver tumors, but via metabolism in the case of NMBzA, or via spontaneous decomposition at physiological pH in the case of MNU, both compounds produce the methanediazonium ion and methylate hepatic DNA. Here we have compared quantitatively the ability of NDMA, NMBzA, and MNU to cause lethal injury to hepatocytes in vivo and to produce O6-methylguanine in hepatic DNA. Neither NMBzA nor MNU produced hepatotoxicity in the rat even at doses as high as 667 mumol/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 O6-methylguanine levels were additive when NDMA and MNU were administered together. These results appear to rule out the involvement of DNA methylation in lethal hepatocyte injury by NDMA.