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Comparative Metabolism in Vitro of a Novel Carcinogenic Polycyclic Aromatic Hydrocarbon, 1,2,3,4-Tetrahydro-7,12-dimethylbenz[a]anthracene, and Its Two Regioisomeric B-Ring Fluoro Analogues¹

College of Pharmacy, Division of Medicinal Chemistry and Pharmacognosy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210

A novel biotransformation pathway likely exists for carcinogenic 1,2,3,4-tetrahydro-7,12-dimethylbenz[a]anthracene (THDMBA), since this A-ring-reduced polycyclic aromatic hydrocarbon does not have an aromatic bay-region. The comparative metabolism of THDMBA, a noncarcinogenic 5F analogue, and a more carcinogenic 6F-THDMBA species was examined to determine potential DNA-bonding metabolites. Rat liver microsomes from phenobarbital-treated animals were incubated in the presence of THDMBA (or fluoro-THDMBA), NADPH, and O₂. Metabolic products and the parent compound were extracted into organic solvent and analyzed/purified using reversed-phase high-performance liquid chromatography. Structure identification of metabolites using proton nuclear magnetic resonance, mass spectroscopy, and ultraviolet/visible spectroscopy indicated that hydroxylations at benzylic C₁ and at the C₇- and C₁₂-CH₃ functions are major oxidation products of THDMBA. Major metabolites for the noncarcinogenic 5F-THDMBA are the C₄-hydroxy, C₇-hydroxymethyl, and C₁₂-hydroxymethyl derivatives. However, the potent carcinogen 6F-THDMBA only yielded major hydroxylation products at C₁ and C₁₂-CH₃. These results together with a consideration of the electronic and steric effects of fluorine and the biological activities of these polycyclic aromatic hydrocarbons suggest that hydroxylation at the hindered benzylic C₁ position or the C₁₂-CH₃ group of THDMBA is important for the biotransformation of such polycyclic aromatic hydrocarbons to DNA-bonding species.

¹ Supported by Environmental Protection Agency Grant R814207-01-0 (to D. T. W.); USPHS Grant 2 P30 CA 16058-16A1 awarded by the National Cancer Institute, Department of Health and Human Services; the National Cancer Institute; and National Research Service Award CA-09338, Division of Cancer Prevention and Control (to S. J. R.).

² To whom requests for reprints should be addressed, at 332 L. M. Parks Hall, 500 West 12th Avenue, Columbus, OH 43210-1291.

Received 10/28/91. Accepted 3/24/92.

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