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Molecular Pharmacology, Vol 13, 819-831, Copyright © 1977 by the American Society for Pharmacology and Experimental Therapeutics

Accessibility of Cytochrome P450 in Microsomal Membranes: Inhibition of Metabolism by Antibodies to Cytochrome P450

PAUL E. THOMAS 1, ANTHONY Y. H. LU 1, SUSAN B. WEST 1, DENE RYAN 1, GERALD T. MIWA 1, and WAYNE LEVIN 1

1 Department of Biochemistry and Drug Metabolism, Research Division, Hoffmann-La Roche, Inc., Nutley, New Jersey 07110

Specific antibodies against highly purified cytochrome P450 from phenobarbital (PB)-treated rats and cytochrome P448 from 3-methycholanthrene (MC)-treated rats were produced in rabbits. These antibodies are inhibitors of drug metabolism catalyzed by liver microsomes from untreated rats or from rats treated with PB, MC, or pregnenolone-16agr-carbonitrile (PCN). Microsomal metabolism of five substrates was examined; the extent of antibody inhibition was dependent not only on the source of the antibody and microsomes but also on the specific substrate and the reactions catalyzed. A comparison of the antibody inhibition patterns of the various substrates examined indicates a marked difference in the proportions of the different forms of cytochrome P450 present in liver microsomes from untreated and PB-, MC-, and PCN-treated rats. Antibody inhibition of microsomal metabolism indicates that the membrane-bound terminal oxidase, cytochrome P450 or P448, is at least partially exposed to the hydrophilic environment on the exterior of microsomal membranes.

Note:
ACKNOWLEDGMENTS We thank Ms. Candy Caso and Ms. Carla Cable for help in preparing the manuscript.

Submitted on November 22, 1976
Accepted on April 4, 1977




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Copyright © 1977 by the American Society for Pharmacology and Experimental Therapeutics