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Molecular Pharmacology, Vol 16, 1011-1018, Copyright © 1979 by the American Society for Pharmacology and Experimental Therapeutics

Catalytic Activity and Stereoselectivity of Purified Forms of Rabbit Liver Microsomal Cytochrome P-450 in the Oxygenation of the (-) and (+) Enantiomers of trans-7,8-Dihydroxy-7,8-Dihydrobenzo[agr]Pyrene

J. DEUTSCH 1, K. P. VATSIS 1, M. J. COON 1, J. C. LEUTZ 1, and H. V. GELBOIN 1

1 Chemistry Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20014 and Department of Biological Chemistry, Medical School, The University of Michigan, Ann Arbor, Michigan 48109

Purified forms of rabbit liver microsomal cytochrome P-450 (phenobarbital-inducible P-450LM2 and beta-naphthoflavone-inducible P-450LMLM4), were examined for catalytic activity in the conversion of the (-) and (+) enantiomers of trans-7,8-dihydroxy-7,8-dihydrobenzo-[a]pyrene to stereoisomeric, highly reactive and mutagenic 7,8-dlhydroxy-9,10-oxy-7,8,9,10-tetrahydrobenzo[agr]pyrenes. In the reconstituted enzyme system, P-450LMLM4 from both phenobarbital- and beta-naphthoflavone-induced animals has much higher catalytic activity than P-450LMLM2 with either enantiomer of the trans-7,8-diol. Both forms of the cytochrome exhibit greater activity toward the (-) than the (+) isomer of the substrate, but this is more striking with P-450LMLM4. The relative amounts of diol-epoxides formed from either enantiomer of the substrate differ markedly with the form of the cytochrome used. P-450LMLM2 gives somewhat more diol-epoxide I than diol-epoxide II with both substrates. In contrast, P-450LMLM4 gives almost exclusively diol-epoxide I from the (-)trans-7,8-diol and more diol-epoxide II than diol-epoxide I from the (+)trans-7,8-diol. Thus, P-450LMLM4 is highly stereospecific in oxygenating at the 9,10 double bond, regardless of the absolute configuration of the hydroxyl groups at the 7 and 8 positions of the substrate.

Note:
ACKNOWLEDGMENTS The authors wish to thank Sylvia B. Dahl for purifying cytochrome P-450 and Barbara M. Michniewicz for purifying the reductase.

Submitted on April 16, 1979
Accepted on July 2, 1979




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