These results are in agreement with a Unified Theory for PAH Carcinogenicity which predicts in vivo generation of a proximate benzylic alcohol metabolite from the 3-MC procarcinogen and conjugation with a moiety such as sulfate intended for rapid urinary excretion. The carcinogenic hydrocarbon 3-methylcholanthrene (3-MC) has a methyl-analogous function at its meso-anthracenic center in the form of a dimethylene bridge, and treatment of this compound with the one electron transfer oxidizing reagent ferric ferricyanide, Fe III(Fe III(CN) 6), in mixed aqueous-organic media generated multiple oxygenated species, many of which duplicate those found in mammalian metabolism including known carcinogens 1-hydroxy-3MC and 1-keto-3MC. One electron transfer oxidation has long been proposed as a route to the ultimate electrophilic and carcinogenic metabolites of both methylated and non-methylated polycyclic aromatic hydrocarbons (PAH).
In this paper, these observations have been extended to include 9-sulfooxymethylanthracene as an ultimate electrophilic and carcinogenic form of 9-hydroxymethylanthracene. Recent studies, in a complete carcinogenic model, demonstrate that a number of sulfuric acid ester derivatives are more potent than their hydroxymethyl precursors by repeated subcutaneous injection in female Sprague-Dawley rats.
Activation of hydroxymethyl derivatives, including 9-hydroxymethylanthracene, to electrophilic mutagens has been shown to be catalyzed by 3′-phosphoadenosine-5′-phosphosulfate-dependent sulfotransferase activity. The common final step in a chain of enzymatic substitution reactions is the formation of an aralkylating agent bearing a good leaving group. The observations are in agreement with a unified hypothesis which predicts that electrophilic hydroxymethyl sulfate esters and closely related aralkylating agents are major ultimate carcinogenic forms of most, if not all, carcinogenic alkyl-substituted and even unsubstituted carcinogenic polycyclic aromatic hydrocarbons. The role of electrophilic hydroxymethyl sulfate esters in the metabolic activation, DNA-damage, mutagenicity, and complete carcinogenicity of polycyclic aromatic hydrocarbons has been elucidated considerably in recent years.
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