Accessibility of cytochrome P450 in microsomal membranes: inhibition of metabolism by antibodies to cytochrome P450
Thomas, P.E.; Lu, A.Y.; West, S.B.; Ryan, D.; Miwa, G.T.; Levin, W.
Molecular Pharmacology 13(5): 819-831
1977
ISSN/ISBN: 0026-895X PMID: 895718 Document Number: 112309
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 were inhibitors of drug metabolism catalyzed by liver microsomes from untreated rats or from rats treated with PB, MC or pregnenolone-16.alpha.-carbonitrile (PCN). Microsomal metabolism of 5 substrates were examined; the extent of antibody inhibition was dependent on source of the antibody and microsomes as well as on the specific substrate and reactions catalyzed. A comparison of antibody inhibition patterns of various substrates examined indicates a marked difference in 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.