Variation in route of microsomal activation of 7,12-dimethylbenz [a]anthracene with substrate concentration +

The nature of the metabolites of 7,12-dimethylbenz[a]anthracene (DMBA) binding to DNA in the presence of Aroclor-induced rat liver microsomes is not affected by the presence or absence of magnesium ions, but is dependent on the concentration of the hydrocarbon. At high concentrations of DMBA, the primary route of metabolic activation is through the K-region oxide while, at low concentrations of DMBA, activation is through other routes. A small proportion of these latter products elute from Sephadex LH-20 columns with mouse embryo cell [14C]DMBA-DNA adducts which are known to arise through reaction of the bay region diol-epoxide of DMBA with cellular DNA. In contrast to the dose-dependence of activation of DMBA by microsomes, the binding of this carcinogen to DNA in intact cultured mouse embryo cells is not qualitatively influenced by concentration over a forty-fold dose range. These findings suggest limitations in the use of microsomal systems as models for target tissue activation.