The metabolism of formyl-substituted benzanthracenes to hydroxymethyl metabolites in rat liver in vitro and in vivo.
Hydroxylation of benzylic methyl carbon atoms on drugs and carcinogenic polycyclic aromatic hydrocarbons (PAHs) forms benzylic alcohols. Many carcinogenic and mutagenic PAHs bear a primary or secondary benzylic hydroxyl group attached to the meso-region of the molecule. According to the unified theory, PAHs bearing a benzylic hydroxyl group are proximate carcinogenic metabolites. This paper demonstrates that carcinogenic benz[a]anthracenes bearing a formyl group at the meso-region undergo enzymatic reductive metabolism to the corresponding carcinogenic benzylic alcohol in vitro and in vivo. The unified theory would then predict sulfuric acid esterification of such benzylic alcohols as the final common step in their metabolic activation to generate ultimate electrophilic benzylic carbocations. Finally, oxidative metabolism of 7-formylbenz[a]anthracenes gives rise to corresponding carboxylic acids and other oxygenated metabolites that are carcinogenically inert. Thus, oxidative metabolism of meso-region formyl compounds represents an avenue for the elimination of the carcinogen in a detoxified form.
Horn
Jamie
J
Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington, KY 40536-0298, USA.
Flesher
James W
JW
Lehner
Andreas F
AF
D000818:Animals; D001551:Benz(a)Anthracenes / Q000493:pharmacokinetics*; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D001551:Benz(a)Anthracenes; D002273:Carcinogens