Carcinogen-DNA interaction: differential effects of distamycin-a and spermine on the formation of 7-methylguanine in DNA by N-methyl-N-nitrosourea, methylmethanesulfonate, and dimethylsulfate.
Experiments were designed to determine whether DNA conformation and sequence play any role in its methylation by N-methyl-N-nitrosourea, methylmethanesulfonate, and dimethylsulfate, agents that are known to methylate DNA by different mechanisms but yield 7-methylguanine as the major product. The approach taken was to bind ligands to DNA that interact with it stereospecifically and to study their effect on the formation of 7-methylguanine by the three methylating agents. The results indicate that both distamycin A and spermine shielded the formation of 7-methylguanine in vitro in rat liver DNA by N-methyl-N-nitrosourea but not by methylmethanesulfonate or dimethylsulfate; they did not, however, protect 2-deoxyguanylic acid against methylation by N-methyl-N-nitrosourea. Based on the mechanism by which the methylating agents and the ligands react with DNA, these results are interpreted to suggest that 1) guanines methylatable at the N-7 position by N-methyl-N-nitrosourea are located at, or close to, the binding sites of the ligands, probably the A-T-rich regions, and those methylatable by methylmethanesulfonate and dimethylsulfate are distal to these regions, and/or 2) the conformation DNA assumes in the presence of distamycin A or spermine permits methylation by methylmethanesulfonate and dimethylsulfate but not by N-methyl-N-nitrosourea. The study implicates DNA structure and/or its sequences in carcinogen-DNA interaction.
D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism*; D004214:Distamycins / Q000494:pharmacology*; D004347:Drug Interactions; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D008745:Methylation; D008770:Methylnitrosourea / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D013096:Spermine / Q000494:pharmacology*; D013463:Sulfuric Acid Esters / Q000494:pharmacology
D002273:Carcinogens; D004214:Distamycins; D011758:Pyrroles; D013463:Sulfuric Acid Esters; D013096:Spermine; D006147:Guanine; C008450:7-methylguanine; D008770:Methylnitrosourea; C030000:stallimycin; D004247:DNA; D008741:Methyl Methanesulfonate; C007482:dimethyl sulfate