Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.16.2 (PCP)
 3,761 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The interaction between phencyclidine (PCP) and its pyrolysis product, 1-phenylcyclohexene (PC), at metabolic level was evaluated in Swiss male mice (21-24 g). PC (1.1, 2.2 and 4.4 mmol/kg/day for 4 days, IP, in corn oil) treatment to mice induced the in vitro metabolism (p less than 0.05) of amidopyrine (17%), aniline (12%), phenacetin (62-100%), pentobarbital (20-26%), PCP (25-80%) and benzo[a]pyrene (81-147%) in the 9000 g liver fraction and the hepatic microsomal contents of cytochrome P-450 (18-42%). The induction of the mixed function oxygenase (MFO) system was consistent with the decreases in the concentrations of IP administered pentobarbital (0.27 mmol/kg, in saline) and PCP (16.4, 32.8 and 65.6 mumol/kg, in saline) in the serum, brain, liver and kidneys of PC pretreated mice. At 1 hr after the above doses of PC, the in vitro metabolism of amidopyrine, aniline, or phenacetin was not inhibited. However, the biotransformation of benzo[a]pyrene was inhibited by 33 to 45%. Though PC after a single dose did not alter the tissue concentrations of PCP, it increased the pentobarbital concentrations in the tissues studied (p less than 0.05). These results indicate that PC has a potential to induce the MFO system after the 4-day treatment. This property of PC plays an important role in the reduction of the action of PCP by enhancing its metabolism, thereby decreasing its tissue levels.
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PMID:Interaction between phencyclidine and its pyrolysis product, 1-phenylcyclohexene. 322 28

PCP is metabolized extensively in the body via a variety of metabolic routes. Biotransformation is a major mechanism of PCP elimination in humans and termination of PCP action in mice. In general, PCP metabolites are less active pharmacologically than PCP itself. Primary metabolism involves hydroxylation of the alicyclic rings at several carbon atoms by cytochrome P-450-mediated monooxygenase. Hydroxylation of the aromatic ring seems to be less likely and has not been conclusively demonstrated. Hydroxylation of PCP at carbon 2 of the piperidine ring to form the unstable carbinolamine leads to formation of a series of polar, open-ring compounds. Monohydroxylated metabolites are conjugated with glucuronic or sulfuric acid, or are further hydroxylated to dihydroxy derivatives that can also be subject to conjugation. Formation of highly reactive electrophilic metabolites of PCP have been demonstrated in vitro in microsomal preparations. Covalent modification of tissue macromolecules by reactive intermediates can be responsible for suicide inactivation of cytochrome P-450 and can possibly mediate some long-term toxic effects of PCP. PCP inhaled by cigarette smoking is metabolized via similar routes. About 50% of the PCP in cigarette smoke is converted to PC, a major product of thermal degradation of PCP. PC and its hydroxylated and conjugated metabolites appear to contribute little to the pharmacology or acute toxicity of PCP.
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PMID:Biotransformation of phencyclidine. 391 38

The in vitro metabolism of phencyclidine by rabbit liver 9000g supernatant fraction produces primarily three known hydroxylated metabolites-namely, 4-phenyl-4-piperidinocyclohexanol, 4-(4'-hydroxypiperdino)-4phenylcyclohexanol, and 1-(1-phenylcyclohexyl)-4-hydroxypiperidine-plus a new metabolite formed by oxidative scission of the piperidine ring yielding an aminoalcohol, and much smaller amounts of five unidentified metabolites. Incubation with 50% deuterium-labeled PCP indicates that these compounds are metabolites by monitoring the resulting doublets found in their mass spectra. The time, cofactor, and protein-dependent formation of these compounds confirms that they are indeed, metabolites. DPEA inhibits the production of the four quantitated metabolites with maximal I50 values of approximately 50 microM, implying the involvement of cytochrome P-450 in these reactions.
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PMID:The metabolism of phencyclidine by rabbit liver preparations. 611 40

Incubation of phencyclidine (PCP) with rabbit liver microsomes resulted in NADPH-dependent loss of N-demethylase activity accompanied by reduction in microsomal cytochrome P-450 content. This effect was concentration-dependent, exhibited pseudo-first order kinetics, and was irreversible, thus exhibiting characteristics of "suicide substrate" inhibition. Cyanide ions at low concentrations, which have been used to trap the iminium intermediate of PCP metabolism as its cyano adduct, antagonized the inhibition of N-demethylase by PCP. PCP iminium ions were effective inhibitors of microsomal enzyme activity but required NADPH. These results support our suggestions that iminium ion formation is an intermediary step in the bioactivation of PCP leading to reactive electrophilic species.
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PMID:Metabolism-dependent inactivation of liver microsomal enzymes by phencyclidine. 614 66

The in vitro metabolism of phencyclidine (PCP) was investigated in 9000 g supernatant fractions of both control and PCP-, ketamine-, ethanol-, phenobarbital- or isosafrole-pretreated rats. Levels of PCP, trans-4-phenyl-4-piperidinocyclohexanol (I), 1-(1-phenylcyclohexyl)-4-hydroxypiperidine (II), N-(5-hydroxypentyl)-1-phenylcyclohexylamine (IX), and 5-(1-phenylcyclohexylamino)-valeric acid (X) were monitored by gas chromatographic analysis in all cases. The inhibition of metabolism by N2, CO, SKF-525A or 2,4-dichloro-6-phenylphenoxyethylamine (DPEA), or deletion of NADPH or protein, implied the involvement of cytochrome P-450 in the reactions. The various inducing agents affected the metabolism of PCP in different ways, implying that at least several isozymes of cytochrome P-450 were involved in the total metabolism. The majority of the consumed PCP was not accounted for by the measured metabolites so that some other metabolic pathways of major quantitative importance must be operative.
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PMID:Induction of phencyclidine metabolism by phencyclidine, ketamine, ethanol, phenobarbital and isosafrole. 670 76

Morphine elicited a dose-related increase in the duration of phencyclidine (PCP)-induced motor incoordination. In the open field behavioral observations, morphine enhanced the PCP-induced decrease in the number of ambulation and rearing. Morphine potentiated the PCP-induced decrease in body temperature. The LD50 of PCP was significantly decreased in the presence of morphine. An opiate antagonist, naloxone, antagonized the morphine-induced effects without influencing the pharmacological actions of PCP itself. The levels of hepatic microsomal cytochrome P-450 and cytochrome b5 and the activities of NADPH dehydrogenase and NADPH cytochrome c reductase were unaffected by morphine treatment. The half-lives of PCP in serum and brain were increased by the concurrent administration of morphine. The ratio of the liver weight to body weight and aniline hydroxylase activity in hepatic microsomal fraction were decreased in the morphine-treated group compared with the control group; this is indicative of a possible reduction in the oxidative metabolism of PCP. The results indicate that acute administration of morphine enhances a variety of pharmacological effects of PCP; an inhibition of PCP disposition by morphine may be a mechanism involved in this process.
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PMID:Effect of morphine on the responses to and disposition of phencyclidine in mice. I. Enhancement of phencyclidine effects by acute morphine administration. 684 96

Development of tolerance to phencyclidine (PCP) was assessed in male ICR mice, using motor incoordination as a parameter. The implantation of a PCP (1-3 mg/day/mouse for 1-5 days)-containing osmotic minipump, induced tolerance, as evidenced by a gradual reduction of the duration of motor incoordination. The degree of tolerance exhibited dose and time dependency. Even after the removal of the PCP pump (1 mg/day/mouse for 5 days), the tolerance remained to the same degree for at least 4 days. The hepatic microsomal cytochrome P-450, cytochrome b5 and nicotinamide adenine dinucleotide phosphatase (NADPH)-cytochrome c reductase activities were found to be elevated in tolerant mice (2 mg/day/mouse for 5 days). The half-life of PCP in the brains of tolerant mice was likewise decreased. These data indicate a dispositional tolerance for PCP. It appears that the administration of PCP by the osmotic minipump offers a convenient method for inducing PCP tolerance.
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PMID:Development of dispositional tolerance to phencyclidine by osmotic minipump in the mouse. 710 47