Guanine N7-alkylation in mice in vivo by metrifonate - discussion of possible genotoxic risk in mammals.

Following intraperitoneal administration to male mice (strain AB Jena/Halle) of 14CH3-labelled metrifonate, 22 Ci/mol, in dosages of 0.48, 0.40 and 0.065 mmol/kg, DNA from liver and kidneys was analysed for 14C in N-7 methylguanine (7-MeG). The extent of methylation in liver was found to be maximal at 6 hrs after injection in amounts of 6-8 and 0.8 mumol 7-MeG/mol guanine for the high and the low dose, corresponding to a covalent binding index CBI 4-5. The half-life of excretion of 7-MeG was 5 hrs for the high and 15 hrs for the low dose. The extent of methylation at 0-6 of guanine was estimated to be around 0.002-0.01 mumol 0-6 MeG/mol guanine. Data from references concerning methyl methanesulfonate and dimethyl sulfate are compared with those of metrifonate and the genotoxic response of methylating and non-methylating metabolites is discussed.