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 cytochrome P450-mediated oxidative demethylenation of the benzo-1,3-dioxoles (methylenedioxyphenyl compounds, MDPs), methylenedioxybenzene (MDB), methylenedioxyamphetamine (MDA), and methylenedioxymethamphetamine (MDMA), by rabbit liver microsomes and cytochrome P450IIB4 (CYP2B4) was examined. Material balance studies indicated that demethylenation to catechol derivatives is a major metabolic pathway for MDB, MDA and MDMA. The reactions required NADPH and were inhibited by CO/O2 (4:1, v/v). Biphasic double-reciprocal plots of MDMA, MDA and MDB oxidation suggested participation of more than one isozyme of cytochrome P450 in the reaction. Phenobarbital (PB) induction was selective in that the Vmax values for MDB were increased but not those for MDA and MDMA. Exposure of liver microsomes from PB-pretreated animals to phencyclidine (PCP) markedly suppressed MDB oxidation but had little effect on MDA and MDMA demethylenation. Reconstitution experiments with CYP2B4 demonstrated that MDB is a good substrate for the isozyme; but the relative demethylenation activities for MDA and MDMA were 1 and 2% of that for MDB. These results indicate that the PB-inducible isozymes such as CYP2B4 appear to play an important role in MDB demethylenation, whereas MDA and MDMA oxidation is mediated mainly by constitutive isozymes.
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PMID:Metabolism of methylenedioxyphenyl compounds by rabbit liver preparations. Participation of different cytochrome P450 isozymes in the demethylenation reaction. 167 3

Three homologues of 1-(1-phenylcyclohexyl)piperidine (PCP) containing the five-, six-, and seven-membered heterocyclic ring (1-(1-phenylcyclohexyl)pyrrolidine (PCPY), PCP, 1-(1-phenylcyclohexyl)hexamethyleneimine (PCHMI) were preincubated with microsomes from phenobarbital-induced rabbit liver. The microsomes were then diluted, an additional charge of NADPH was added, and N-demethylation of benzphetamine was determined. Preincubation of the microsomes with the analogues lowered P-450-dependent N-demethylation by a process that was NADPH-dependent, reduced CO binding to microsomes, and followed pseudo-first order kinetics. The relative rates of inactivation, PCP greater than or equal to PCPY greater than PCHMI, agreed with the order of inhibition of CO binding to reduced microsomes. This mechanism-based inhibition was not observed with phenylcyclohexylamine, indicating that the substituted nitrogen is necessary. The substituted nitrogen must also be part of a heterocyclic ring since the diethylamino analogue of PCP did not exhibit the same type of inhibition a heterocyclic ring is involved. These trends correlated with the expected relative stabilities of the cyclic form of the carbinolamine suggesting that the inhibitory species was formed from the closed ring isomer.
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PMID:Mechanism-based inhibition of cytochrome P-450 by heterocyclic analogues of phencyclidine. 289 81

The in vitro effects of THC on the metabolism of PCP by rat liver were determined. Samples containing 1 mM PCP were incubated for 1 hr at 37 degrees C with an NADPH-generating system containing 10,000 X g supernatant or Ca++-precipitated rat liver microsomes. These incubations were carried out in the presence or absence of THC and at the end of 1 hr, PCP metabolites were determined by gas chromatography. In the presence of 0.1, 0.05, 0.025 and 0.0125 mM THC, the production of 1-(1-phenyl-4-hydroxycyclohexyl)piperidine (metabolite I) by the 10,000 X g supernatant was decreased by 46, 29, 23 and 16% respectively. Similarly, production of 1-(1-phenylcyclohexyl)-4-hydroxypiperidine (metabolite II) was reduced significantly by 58, 44, 34 and 23% with the respective concentrations of THC. However, the production of 1-phenylcyclohexylamine (metabolite III) was increased by 18, 32, 30 and 22% with 0.1, 0.05, 0.025 and 0.0125 mM THC. Incubations with Ca++-precipitated liver microsomes revealed similar trends in PCP metabolism in the presence or absence of THC. Metabolites I and II were reduced by 62 and 67% by 0.1 mM THC. Another concentration of THC (0.025 mM) caused a 50 and 62% decrease in I and II. These observations suggest that THC alters the in vitro microsomal metabolism of PCP.
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PMID:Metabolic interactions of phencyclidine (PCP) and delta 9-tetrahydrocannabinol (THC) in the rat. 302 81

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

Cytochrome P4502B1, the major phenobarbital-inducible isozyme in the rat liver, is inactivated by phencyclidine (PCP). Incubation of PCP with purified P4502B1 in the reconstituted enzyme system with NADPH-cytochrome P450 reductase and phospholipid resulted in a marked loss of activity as measured using a secondary incubation mixture for 7-ethoxycoumarin O-deethylase activity. The loss of activity required NADPH and PCP, and the activity decreased in a time-dependent, pseudo-first-order process indicative of mechanism-based inactivation. The rate constants for inactivation were dependent on the PCP concentrations and displayed saturation kinetics. A KI = 3.8 microM and kinact = 0.12 min-1 were determined for the inactivation by PCP. The partition ratio calculated from a plot of the percentage activity remaining after 45 min vs. the concentration ratios of PCP to P450 was 45. Although 90% of the catalytic activity was lost after a 45-min incubation, little loss was seen in the optical spectrum at 418 nm or in the ability of the reduced enzyme to bind CO. The inactivation was not inhibited by the addition of cyanide, whereas substrates such as 7-ethoxycoumarin protected against the inactivation. The iminium ion of PCP, an oxidative metabolite, inactivated P4502B1 in the same fashion as PCP. These results demonstrate that PCP is an efficient mechanism-based inactivator of rat liver P4502B1 and does not inactivate by modification of the heme moiety.
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PMID:Mechanism-based inactivation of rat liver cytochrome P4502B1 by phencyclidine and its oxidative product, the iminium ion. 749 43

The bacterial enzyme PCP 4-monooxygenase from Flavobacterium sp. strain ATCC 39723 catalyzes the oxygenolytic removal of the first chlorine from pentachlorophenol. PCP 4-monooxygenase is an FAD binding, NADPH requiring oxygenase, with similar functional domains as other bacterial flavoprotein monooxygenases specific for phenolic substrates. However, the definitive proof for the singular role of an oxygenolytic elimination of the primary chlorine from pentachlorophenol by Flavobacterium sp. has awaited the development of a genetic system whereby targeted mutagenesis via allelic exchange could be carried out with the corresponding gene from PCP 4-monooxygenase, pcpB. We report the development of a genetic system for Flavobacterium sp. strain ATCC 39723, and its application in targeted mutagenesis of the pcpB allele for elimination of PCP 4-monooxygenase activity.
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PMID:Verification of the role of PCP 4-monooxygenase in chlorine elimination from pentachlorophenol by Flavobacterium sp. strain ATCC 39723. 861 98

Phencyclidine (PCP) inactivates the 7-ethoxy-4-trifluoromethylcoumarin O-deethylase activity of P4502B1 in a reconstituted system containing NADPH-cytochrome P450 (P450) reductase (reductase) and L-alpha-phosphatidylcholine, dilauroyl in a time-, concentration-, and NADPH-dependent manner. Catalytic activity of the enzyme could not be restored upon reconstitution with fresh reductase, indicating that the effect was on the P450 and not on the reductase. Although the kinetics suggested that PCP would be classified as a classical mechanism-based inactivator, protection against inactivation of P450 by PCP by the presence of an exogenous nucleophile, such as glutathione (GSH), indicated otherwise. There was no loss of spectrally detectable P450 associated with inactivation either in the presence or absence of GSH. When radiolabeled PCP was used to inactivate the enzyme and the reaction mixture analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, radioactivity was found to be associated with P450, reductase, and catalase that had been added to protect against oxidative damage. When GSH was included in the reaction mixtures, analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis demonstrated a marked decrease in the binding to all three proteins. Correspondingly, analysis of the components of the inactivated sample by reversed-phase HPLC demonstrated that radioactivity was associated with P450, reductase, and catalase, and that there was a marked decrease in the labeling of all three proteins in the presence of GSH. The stoichiometry of binding of radiolabeled PCP to the proteins in the incubation mixture in the absence of GSH was 4:1. In the presence of GSH, no significant amount of radioactivity was incorporated into the proteins. An anti-PCP metabolite antibody was used to detect PCP metabolite adducts bound to the inactivated enzyme by Western blot analysis. The antibody recognized adducts bound to P450, reductase, and catalase. In the presence of GSH, there was a decrease in immunoreactivity, although binding of PCP to all three proteins was still detected. Because the added nucleophile protects against inactivation and protein labeling by PCP, these data suggest that the reactive intermediate may escape from the active site and attack other sites on the P450, as well as other proteins in the milieu.
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PMID:Metabolic inactivation of cytochrome P4502B1 by phencyclidine: immunochemical and radiochemical analyses of the protective effects of glutathione. 902 55

These studies examined the microsomal brain metabolism of phencyclidine (PCP) in male and female Sprague-Dawley rats. Several monohydroxylated metabolites of PCP were detected including cis- and trans-1-(1-phenyl-4-hydroxycyclohexyl)piperidine (c-PPC and t-PPC) and 1-(1-phenylcyclohexyl)-4-hydroxypiperidine (PCHP). The in vitro formation of these metabolites required NADPH and was inhibited by carbon monoxide. c-PPC was formed in the male and female brain microsomes at rates of 7.1 +/- 1.3 and 5.7 +/- 1.1 fmol/min per mg, respectively, while t-PPC was formed at rates of 16.2 +/- 3.3 and 16.5 +/- 4.2 fmol/min per mg. PCHP had the highest formation rate at 50.7 +/- 8.9 and 48.2 +/- 8.8 fmol/min per mg, respectively. Although previous studies with rat liver microsomes find higher levels of PCP metabolism in male rats and the formation of an irreversibly bound metabolite in male rats, the present study of brain metabolism found no sex differences in brain metabolism. The formation of PCP metabolites in male rat livers is at least partially mediated by the male-specific isozyme CYP2C11, and possibly CYP2D1. Nevertheless, the formation of the major brain metabolite, PCHP, was not inhibited by an anti-CYP2C11 or an anti-CYP2D6 antibody. However, PCHP formation was inhibited by drug inhibitors of CYP2D1-mediated metabolism, suggesting the involvement of a CYP2D isoform. These data indicate brain metabolism of PCP is significant, but unlike the liver it is not sexually dimorphic.
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PMID:Brain microsomal metabolism of phencyclidine in male and female rats. 918 40


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