ARYLAMINE-DNA ADDUCT CONFORMATION IN RELATION TO MUTAGENESIS

A considerable body of evidence has indicated that local conformationa l alterations induced by DNA adducts may provide the molecular basis f or differences in mutational specificities exhibited by structurally s imilar adducts. To elucidate the relationships between adduct structur e and mutation induction, the ability of several single-ring arylamine s present in tobacco smoke (i.e., methylanilines, dimethylanilines, an d ethylanilines) to form DNA adducts was investigated. In all cases, t he major adducts were C8-substituted deoxyguanosine derivatives, which is consistent with what has been observed with more carcinogenic aryl amines, such as 2-aminofluorene and 4-aminobiphenyl. Spectroscopic and theoretical data on the adducts indicated conformational differences depending upon the location of the alkyl substituents. Adducts contain ing alkyl groups ortho to the amine function (e.g., 2-methylaniline) h ad a greater percentage of syn conformers about the glycosyl bond than those not bearing such groups. Arylamines with ortho alkyl substituen ts tend to be more mutagenic and tumorigenic than analogues not contai ning an ortho alkyl substituent. This increase in biological activity may be due in part to the greater propensity of ortho alkylated adduct s to adopt a syn conformation.