METABOLIC ACTIVATION OF MONOMETHYLBENZ ANTHRACENES

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Methylbenz(a)anthracenes (MBAs) have been found in cigarette smoke condensates, stack gas and roofing tar extracts and are potentially environmental hazards to man. Among the twelve isomeric MBAs, 7-MBA is the most active skin carcinogen, 6-, 8-, 12-MBA are less active, and other MBAs are either inactive or slightly active when injected subcutaneously or painted on the skin of rats or mice. The molecular basis for the different carcingenicities of the twelve MBAs is currently unknown. Since MBAs require metabolism to exert their carcinogenicity, the possible differences in their metabolic pathways which may account for their relative carcinogenic potencies will be investigated. The proposed studies are: (1) synthesis of unlabeled and tritium-labeled MBAs; (2) detailed regioselective and stereoselective metabolic studies of each MBA in rat liver microsomes in vitro and in mouse skin in vivo; (3) identification of metabolites formed enzymatically from each MBA by high-performance liquid chromatography, ultraviolet and fluorescence spectrophotometry, mass and nuclear magnetic resonance spectroscopy, and spectropolarimetry; (4) studies on the regioselectivity and stereoselectivity of cytochrome P-450 isozymes and epoxide hydrolase of rat liver microsomal preparations in vitro and in mouse skin in vivo by analyzing the epoxide and dihydrodiol metabolites formed by using molecular oxygen-18 and oxygen-18 water and by chiral stationary phase high-performance liquid chromatography; (5) large-scale preparations of MBA metabolites by enzymic and/or chemical methods; (6) determination of relative mutagenic activities of MBA and metabolites with Salmonella typhimurium tester strain TA100; (7) DNA binding activities of MBAs in mouse skin in vivo; and (8) tumor-initiating activities of the MBAs and their metabolites on mouse skin. These studies will provide detailed understanding of the structure-activity relationships of the twelve MBAs and the molecular basis of their relative carcinogenic potencies.