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Metabolism of 5-Methylchrysene and 6-Methylchrysene by Human Hepatic and Pulmonary Cytochrome P450 Enzymes¹

Division of Chemical Carcinogenesis, American Health Foundation, Valhalla, New York 10595 [W. K., S. A., M. E. S., S. S. H.]; Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146 [Y-F. U., H. Y., T. T., F. P. G.]; and Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 [T. T.]

The metabolism of environmentally occurring methylated polynuclear aromatic hydrocarbons by human cytochrome P450 (P450) enzymes has not been examined previously. We compared the metabolism of the tobacco smoke constituents 5-methylchrysene (5-MeC), a strong carcinogen, and 6-MeC, a weak carcinogen, in 18 hepatic and 11 pulmonary human microsomes. Major metabolites of 5-MeC were its proximate carcinogen trans-1,2-dihydroxy-1,2-dihydro-5-methylchrysene (5-MeC-1,2-diol), as well as 5-MeC-7,8-diol were formed stereoselectively, with the R,R enantiomers predominating. Major metabolites of 6-MeC were 6-MeC-1,2-diol, bay region dihydrodiols, phenols, and 6-(hydroxymethyl)chrysene. 6-MeC-1,2-diol was also formed stereoselectively in the 1R,2R configuration. All human liver samples formed the proximate carcinogenic 1,2-diols (0.2–2.3 pmol/mg protein/min for 5-MeC and 0.3–3.1 pmol/mg protein/min for 6-MeC). Comparable results were obtained in pulmonary microsomes, but the extent of metabolism was less than in the hepatic samples, and only 4 of 11 samples showed activity. Catalytic activities known to be associated with specific P450s were analyzed in each hepatic sample and correlated with levels of 5-MeC and 6-MeC metabolites in the same samples. The results of the correlation analysis indicated that P450s 1A1 and 1A2 were active in the formation of 5-MeC-1,2-diol and 6-MeC-1,2-diol, as well as several other metabolites resulting from ring oxidation. The formation of the hydroxymethyl metabolites was catalyzed by P450 3A4 (for 5-MeC) or P450s 3A4 and 1A2 (for 6-MeC). Experiments with chemical inhibitors and antibodies supported these results. The metabolism of 5-MeC and 6-MeC was also investigated using purified recombinant human P450s 1A1, 1A2, 2C10, 2D6, 2E1, 3A4, and 3A5. P450s 1A1, 1A2, and 2C10 had higher activities than the other enzymes for ring oxidation of 5-MeC and 6-MeC, whereas P450s 1A2 and 3A4 were more active than the other enzymes for methyl hydroxylation of 6-MeC. Only P450 3A4 showed substantial catalytic activity for methyl hydroxylation of 5-MeC. Collectively, the results of these studies demonstrate that P450s 1A2 and 2C10 are important catalysts of the metabolic activation of 5-MeC and 6-MeC in human liver, whereas P450 1A1 plays a major role in the metabolic activation of these compounds in human lung.

¹ This study was supported by Grants CA-44377 (to S. S. H.), CA-44353 (to F. P. G.), and ES-00267 (to F. P. G.) from the NIH.

² Present address: Department of Food Chemistry and Environmental Toxicology, University of Kaiserslautern, 67663 Kaiserslautern, Germany.

³ Present address: Osaka Prefectural Institute of Public Health, Nakamichi, Higashinari-ku, Osaka 537, Japan.

⁴ Present address: Department of Clinical Pharmacology, Jichi Medical School, Minamikawachi, Tochigi 329-04, Japan.

⁵ To whom requests for reprints should be addressed, at American Health Foundation, I Data Road, Valhalla, NY 10595.

Received 8/28/95. Accepted 11/ 9/95.

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