Selective mechanism-based inactivation of the major phenobarbital-inducible P-450 cytochrome from rabbit liver by phencyclidine and its oxidation product, the iminium compound.
Phencyclidine, 1-(1-phenylcyclohexyl)piperidine, was found in this study to be a mechanism-based inactivating agent for cytochrome P-450 form 2, the major phenobarbital-inducible cytochrome of rabbit liver microsomes. This process is highly selective for P-450 form 2, both in microsomes and in the reconstituted enzyme system, in that forms 3a, 3b, 4, and 6 are not affected. However, phencyclidine iminium ion, an oxidative metabolite, inactivates both P-450 form 2 and form 3b in a metabolism-dependent manner. Both phencyclidine and its iminium ion give biphasic kinetics of inactivation with similar rate constants, which supports the hypothesis that the iminium ion is an intermediate in the inactivation of P-450 form 2 by the parent compound. The absorption of the oxidized cytochrome and of the ferrous-carbonyl complex in the visible spectrum are both decreased upon inactivation by phencyclidine, indicating modification of the heme moiety. Several modified hemes produced by the action of phencyclidine were isolated by HPLC.
Osawa
Y
Y
Department of Biological Chemistry, Medical School, University of Michigan, Ann Arbor 48109.
Coon
M J
MJ
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006418:Heme / Q000302:isolation & purification; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010622:Phencyclidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology*; D011817:Rabbits; D013053:Spectrophotometry
D006418:Heme; C026954:phencyclidine methiodide; D003577:Cytochrome P-450 Enzyme System; D010622:Phencyclidine; D010634:Phenobarbital