Effect of a 12-Methyl Group on the Mutagenic Specificity of 7-Bromomethylbenz[a]anthracene

Abstract

The mutational specificities of the carcinogens 7-bromomethyl-benz[a]anthracene and 7-bromomethyl-12-methylbenz4[a]anthracene were investigated using the shuttle vector pS189 forward mutation assay. It is has been shown that the unsubstituted compound is more reactive with DNA (Rayman, M.P. and A. Dipple, 1973a) and more mutagenic in Chinese hamster V79 cells (Duncan, M.E. and P. Brookes, 1973). However, the 12-methyl derivative has been shown to be substantially more tumorigenic in both mice and rats (Dipple, A. and T.A. Slade, 1971). In the present study, the unsubstituted bromo-compound was nine-fold more mutagenic than the 12- methyl derivative in the p5189 system. The bromo-compounds should form only a single guanine and adenine adduct (unlike the polycyclic aromatic hydrocarbon dihydrodiol epoxides which form both cis and trans adducts). However, more than one mutational change was found at a given site, with the majority of the changes being G-T transversions. The presence of the 12- methyl group substantially increased (5-fold) the fraction of G-C transversions, decreased the number of single base deletions (3-fold), and led to a substantially greater fraction of total mutations being associated with mutational hotspots. It is possible that one or all of these differences account for the greater tumorigenicity of the 12-methyl derivative, despite the greater mutagenicity of the unsubstituted bromo-compound.