The persistence of
O6-methylguanine produced by a single dose of
N-methyl-N-nitrosourea (MNU) was determined in
DNA of various murine tissues and compared with the location of tumours induced by MNU and related alkylating
carcinogens in this species. A/J and C3HeB/FeJ mice received a single
intravenous injection of MNU (10 mg/kg) and were killed at different time intervals ranging from 4 h to 7 days. The rate rate of loss of
O6-methylguanine from brain
DNA was considerably slower than from liver
DNA; tumours have been found in both organs after administration of MNU and other alkylnitrosoureas. There was no difference in the rate of excision from cerebral
DNA of A/J and C3HeB/FeJ mice, although these strains differ significantly in their susceptibility to the neurooncogenic effect of MNU and related
carcinogens. Excision of
O6-methylguanine from hepatic
DNA was significantly slower in A/J than in C3HeB/FeJ mice; both strains habe been found to develop hepatic
carcinomas following MNU administration. Seven days after the injection of 3H-MNU,
O6-methylguanine concentrations were highest in brain and lung
DNA, lowest in the liver, and intermediate in kidney, spleen, small intestine and stomach. The lung is a principal target organ for tumour induction by MNU and other
carcinogens in mice; however, neural tumours are usually induced at a low incidence. The results obtained do not contradict the hypothesis that O6-alkylation of
guanine in
DNA is a critical event in the initiation of tumour induction by
alkylating agents. However, the location of tumours produced in mice does not seem to depend solely on the formation and persistence of O6-alkylguanine in
DNA.