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Molecular Pharmacology, Vol 15, 138-153, Copyright © 1979 by the American Society for Pharmacology and Experimental Therapeutics

Metabolism of Benzo[a]anthracene to Its Tumorigenic 3,4-Dihydrodiol

D. R. THAKKER 1, W. LEVIN 2, H. YAGI 1, D. RYAN 2, P. E. THOMAS 2, J. M. KARLE 1, R. E. LEHR 1, D. M. JERINA 1, and A. H. CONNEY 2

1 Section on Oxidation Mechanisms, Laboratory of Chemistry, National Institute of Arthritis, Metabolism, and Digestive Diseases, National Institutes of Health, Bethesda, MD 20014
2 Department of Biochemistry and Drug Metabolism, Hoffmann-La Roche Inc., Nutley, NJ 07110

The weak carcinogenicity of benzo[a]anthracene may be due to either low amounts of the tumorigenic 3,4-dihydrodiol formed or poor conversion of this diol to the bay-region diol epoxides, i.e., benzo[a]anthracene 3,4-diol-1,2-epoxides. We have investigated the metabolism of benzo[a]anthracene with rat liver microsomes and a highly purified monooxygenase system reconstituted with cytochrome P-448 to determine the relative amounts of the 3,4-dihydrodiol formed. With liver microsomes from induced and uninduced rats, as well as with the purified and reconstituted system in the presence of epoxide hydrase, benzo[a]anthracene was metabolized predominantly to its 5,6- and 8,9-dihydrodiols. Small but significant amounts of the 3,4- and 10,11-dihydrodiols were also detected by chromatographic methods and fluorescence spectrometry. Since only trace amounts of phenols were detected, the arene oxides of benzo[a]amthracene must be good substrates of epoxide hydrase. With the purified and reconstituted system in the absence of epoxide hydrase, only phenols and the K-region 5,6-oxide were found to be metabolites of benzo[a]-anthracene. Moreover, the extent of metabolism of benzo[a]anthracene was substantially reduced in the absence of epoxide hydrase, suggesting that phenolic metabolites are potent inhibitors. Strong inhibition of the metabolism of benzo[a]anthracene by synthetic 5- and 6-hydroxybenzo[a]anthracenes and by a mixture of phenolic metabolites was observed.

Note:
ACKNOWLEDGMENTS The authors wish to thank Mrs. Janet Deyhle for her excellent help in the preparation of this manuscript.

Submitted on June 7, 1978
Accepted on August 7, 1978




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