The Meso-Region Theory of Aromatic Hydrocarbon Carcinogenesis

Abstract

Structure-activity relationships (SAR) demonstrate the importance, for carcinogenic activity in polycyclic aromatic hydrocarbons (PAHs), of substituents at meso-regions of exceptional reactivity whether located in an aromatic nucleus or on a side chain. The simplest SAR is that a majority of carcinogenic hydrocarbons can be classified as anthracene derivatives. The meso-region theory proposes that the chemical and biochemical pathways of activation of both unsubstituted and meso-substituted PAHs are essentially the same. The first biochemical step, in a chain of three substitution reactions, involves the methylation of unsubstituted PAHs, at a meso-center of exceptional reactivity. Hydroxylation of a meso-region methyl group is followed by the formation of a reactive ester (e.g., sulfuric acid ester) bearing a good leaving group, which would be expected to generate a highly reactive carbonium ion. The carbonium ion would be expected to react with critical nucleophiles to initiate the chain of cellular events which results in cancer. When a substituent blocks a meso-region of exceptional reactivity, carcinogenic activity is reduced or abolished.