The Structural Basis for the Production of Cancer and Detoxification by Oxidized Metabolites of Mesoanthracenic Methylated and Non-Methylated Polynuclear Hydrocarbons: a Paradigm Shift

Although many attempts have been made since 1930 to explain the production of cancer in experimental animals by oxidized metabolites of polynuclear aromatic hydrocarbons (PAH) with either molecular structure types ArCH₂X or ArX, the simplest interpretation is that one type must function in experimental animals to produce cancer, whereas the other structural type prevents the production of cancer by formation of detoxification products. The specific predictions of the Unified Theory of carcinogenesis by PAH or PACs (Polynuclear Aromatic Compounds) depends on the validity of the predictions for the production of cancer by PACs with structural types ArCH₂X or ArX. These two structural types have been adopted as crucial models for PAC metabolites by Flesher, Sydnor and colleagues since the 1970s. We were aided by the experiments and strong inferences of Professors Fieser, Fried, Boyland, Sims, and Huggins, and the theoretical studies of a possible structure of the ultimate carcinogen for 7-methylbenz[a]anthracene and closely related hydrocarbons by Brookes and Dipple together with the calculations of Dewar that predict the most reactive centers for substitution reactions in unsubstituted hydrocarbons. Shear in the late 1930s and 1940s was the first to show that meso-aldehydes and meso-methyl-substituted hydrocarbons function as precursors to active compounds with structure type ArCH₂X. The discoveries by Flesher, Sydnor and coworkers demonstrated that biological methylation must take place at the most reactive center in non-methylated hydrocarbons catalyzed by cytosolic SAM-dependent methyltransferases, and the methyl group must subsequently be hydroxylated and conjugated with a good leaving group, if the PAC is to be carcinogenic. This is precisely the same site of special reactivity required for methylation by chemical synthesis as calculated by the Dewar molecular orbital approach. Blocking the reactive center in the aromatic nucleus (in the form of products as ArX) with the same groups attached to the meso-methyl group of methyl-substituted hydrocarbons (in the form ArCH₂X) which produces cancer typically abolishes the production of cancer. Consequently, no theory relating ring oxidation to the production of cancer can account for the fact that substitution of reactive centers in non-methylated hydrocarbons with hydroxy or acetoxy groups, while simultaneously blocking methylation, also abolish its carcinogenic activity. If alternative hypotheses or theories do not cite the fundamental studies of Fieser and of Shear and Leiter there is little possibility that the alternative theory is correct. It seems obvious that most, if not all, hypotheses or theories that attempt to relate ring oxidized metabolites of PAH to the production of cancer have been disproved.