The formation of methylated bases in DNA by dimethylnitrosamine and its relation to differences in the formation of tumours in the livers of GR and C3HF mice

Metabolism of and DNA methylation by dimethylnitrosamine (DMNA) were measured in the livers of GR male and C3Hf male and female mice which showed widely different susceptibilities to tumour formation by this hepatocarcinogen.It was previously shown that continuous DMNA administration results in vascular tumours in the livers of C3Hf female mice, whereas C3Hf males develop a high incidence of hepatomas both after continuous treatment and after a single injection of DMNA to adult animals. GR males showed a low susceptibility to the formation of liver tumours under these conditions.N-demethylation of DMNA by liver microsomes showed similar activity for both C3Hf sexes; but GR males were significantly more active.At 5 and 48 h after a single injection of ¹⁴C]DMNA, the amounts of O⁶-methylguanine (O⁶-MeGua), 7-methylguanine (7-MeGua), 1-methyladenine (1-MeAde) and 3-methyladenine (3-MeAde) were similar for C3Hf males and females, with the possible exception of 7-MeGua which seemed to be slightly higher in the female. O⁶ MeGua disappeared from C3Hf liver DNA with an apparent half-life time of about 24 h. Especially at 48 h after injection, GR liver DNA was methylated to a higher extent than was C3Hf liver DNA. This result, which antiparallels the tumour incidences, may be explained by the differences in rate of N-demethylation of DMNA. where higher 7-MeGua values were found for fasted animals under otherwise identical conditions.The general conclusior to be drawn is that neither the metabolism of DMNA nor DNA methylation by this carcinogen in the livers of male GR and C3Hf male and female mice correlates With the formation of hepatomas after DMNA administration. A possible explanation of the absence of such a correlation between DNA methylation and tumour formation might be that there exists no causal relationship between both events. However, a complicating factor is that the eventual development of a tumour may be influenced by a number of—sometimes decisive—secondary factors like hormonal²⁵ or immunological²⁶ status or the presence of cellular proliferation in target organs^27,28. Evidence from other systems suggests a relationship between inactivating, mutagenic or carcinogenic effects of alkylating agents and their ability to interact with nucleic acids, especially DNA^29,30.