Phencyclidine, a psychotomimetic agent and drug of abuse, is a suicide inhibitor of brain nitric oxide synthase.
Phencyclidine, 1-(1-phenylcyclohexyl)piperidine, was shown in this study to be an effective irreversible inhibitor of brain nitric oxide synthase, the enzyme responsible for the conversion of L-arginine to nitric oxide. The inactivation of nitric oxide synthase was time- and concentration-dependent and required reduced nicotinamide adenine dinucleotide phosphate, a necessary cofactor for nitric oxide synthesis. These results indicate that phencyclidine is metabolized by nitric oxide synthase to reactive intermediates that irreversibly inactivate the enzyme. The inactivation of nitric oxide synthase by xenobiotics, such as phencyclidine, may be pharmacologically and toxicologically important due to the role of nitric oxide in a variety of physiological processes.
Osawa
Y
Y
Laboratory of Chemical Pharmacology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
Davila
J C
JC
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D001921:Brain / Q000201:enzymology*; D003600:Cytosol / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D019001:Nitric Oxide Synthase; D010622:Phencyclidine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D010622:Phencyclidine