Mutational specificities of environmental carcinogens in the lacI gene of Escherichia coli. I. The direct-acting analogue N-nitroso-N-methyl-N-alpha-acetoxymethylamine.
The mutational specificity of N-nitroso-N-methyl-N-alpha-acetoxymethylamine in Escherichia coli has been determined through the DNA sequence characterization of 190 forward mutations in the lacI gene. Consistent with the methylating ability of this compound and the predicted mutagenic potential of O6-methylguanine damage, the predominant mutation was the G:C----A:T transition. An analysis of the neighbouring template revealed a similar 5' flanking sequence influence on G:C----A:T site mutability reported for other direct-acting SN1 alkylating agents. However, a dose-dependency was observed. The preference for transition at guanine residues flanked (5') by a purine over those preceded by a pyrimidine decreased from a ratio of 19:1 (upon 1 mM treatment) to 6:1 (upon 10 mM treatment) and 4:1 (upon 30 mM treatment). Two double G:C----A:T transition mutants were characterized. In addition, this nitrosamine appears to be relatively more efficient at producing other kinds of mutations. In total 19 non-G:C----A:T mutations were identified. These included: A:T----G:C transitions, transversions and frameshifts. The relative contribution of these events was found also to decrease with increasing dose. These results may help explain why the parent carcinogen N-nitroso-N,N-dimethylamine is hepatotropic while other methylating carcinogens, similarly metabolized in the liver, are not.
Horsfall
M J
MJ
Biology Department, York University, Toronto, Ontario, Canada.
Glickman
B W
BW
D001482:Base Composition; D001483:Base Sequence; D002273:Carcinogens / Q000494:pharmacology*; D003001:Cloning, Molecular; D004128:Dimethylnitrosamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004787:Environmental Pollution; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics*; D005796:Genes / Q000187:drug effects*; D005798:Genes, Bacterial / Q000187:drug effects*; D008969:Molecular Sequence Data; D009152:Mutagenicity Tests
D002273:Carcinogens; C014659:methyl(acetoxymethyl)nitrosamine; D004128:Dimethylnitrosamine