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

The metabolism of phencyclidine (PCP) was examined in the isolated perfused lung (lPL), lung microsomes, and liver microsomes of rabbits. The concentration of PCP in the IPL perfusate decreased rapidly with concomitant increases in the concentrations of PCP metabolites. The total rate of PCP metabolite appearance in the perfusate of the IPL was 77.4 nmol/lung/min. The apparent Vmax of PCP metabolism by the lung and liver microsomes were 1.52 and 22.9 nmol of PCP metabolised per mg of microsomal protein per min, respectively. Extrapolated to the whole lung, the apparent Vmax of PCP metabolism by lung microsomes was equivalent to 78.6 nmol of PCP metabolized per lung per min, essentially the same as that for the IPL.
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PMID:Rates of phencyclidine metabolism by the isolated perfused lung, lung microsomes, and liver microsomes of rabbits. 612 35

The in vitro metabolism of 1-3H-phenyl-1-cyclohexene (3H-PC) was studied in a crude microsomal preparation from mouse livers. The major routes of metabolism were allylic hydroxylation, oxidation of the allylic alcohol, and epoxidation-hydrolysis. The following metabolites were identified by comparison with reference compounds: 1-phenyl-1-cyclohexen-3-ol (major metabolite), 1-phenyl-1-cyclohexen-3-one (PC-3-one) (major), 1-phenyl-1-cyclohexen-6-ol (minor), 1-phenyl-1-cyclohexen-6-one (minor), and 1-phenylcyclohexane-1,2-diol (PC-1,2-diol) (minor). An additional metabolite, present in abundant quantities, was formed as a result of both allylic hydroxylation and epoxidation-hydrolysis. This triol contained hydroxyl groups at positions 1 and 2 of the cyclohexane ring but the position of the third hydroxyl group could not be established. PC-3-ol and PC-3-one were found to be somewhat more potent than PC in the inverted-screen test, whereas PC-1,2-diol was less effective. However, all three metabolites were considerably less active than PCP in this test.
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PMID:In vitro metabolism of 1-phenyl-1-cyclohexene, a pyrolysis product of phencyclidine. 613 Sep 24

Incubation of phencyclidine (PCP) with rabbit liver microsomes and Na14CN resulted in the metabolically dependent formation of a 14C-labeled cyano adduct of the drug. After isolation by HPLC, this compound was identified as the alpha-aminonitrile [1-(1-phenylcyclohexyl)-2-cyanopiperidine] derivative of PCP by use of chemical-ionization and gas-chromatographic coupled electron-impact mass spectrometry. Synthetic alpha-aminonitrile exhibited identical chemical properties and comigrated in HPLC and GLC with the metabolism derived cyano adduct. Molecular identification of the adduct formed by cyanide trapping provided evidence for the formation of an iminium ion during PCP metabolism. Quantitative estimation by HPLC demonstrated that the alpha-aminonitrile accounted for over 50% of the PCP metabolized in 30 min by hepatic microsomes in vitro. Metabolism-dependent covalent binding of [3H]PCP to rabbit liver microsomal proteins was inhibited by cyanide ion in a concentration-dependent manner with an IC50 value of 57 microM. The concentrations of cyanide ion used in these experiments did not significantly inhibit the metabolism of PCP. These results support our suggestions that iminium ion formation may represent an important intermediary step in the metabolism of PCP and that such a reactive electrophilic species may be capable of covalent interactions with nucleophilic groupings on microsomal macromolecules.
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PMID:Metabolism of phencyclidine. The role of iminium ion formation in covalent binding to rabbit microsomal protein. 613 Sep 25

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

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

3H-labeled 9-methyl-7-bromoeudistomin D ([3H]MBED), a powerful caffeine-like Ca2+ releaser, binds to the caffeine binding site of terminal cisternae (TC) of skeletal muscle sarcoplasmic reticulum (SR) (Fang, Y-I., Adachi, M., Kobayashi, J., and Ohizumi, Y. (1993). J. Biol. Chem. 268, 18622-18625.) and activates Ca(2+)-induced Ca2+ release (CICR). [3H]MBED, however, bound to rabbit hepatic microsomes with a comparable affinity (Kd = 50 nM) and with a more than 30-fold greater receptor density (Bmax = 350 pmol/mg of protein), compared with those in SR. Caffeine (0.1-10 mM) caused a concentration dependent inhibition of [3H]MBED binding to hepatic microsomes with the IC50 value of 0.3 mM. The mode of inhibition by caffeine was allosteric, indicating that the binding site of the ligand is distinct from but related to that of caffeine. Procaine (1-10 mM), a representative inhibitor of CICR, which suppresses [3H]MBED binding to TC-SR, inhibited ligand binding to hepatic microsomes only slightly. Moreover, ligand binding to the hepatic binding site was not affected by adenosine 5'-(beta, gamma-methylene) triphosphate (AMP-PCP) (10-100 microM), which is an activator of CICR and potentiates [3H]MBED binding to TC-SR. Inhibitors of [3H]MBED binding to liver microsomes other than caffeine were nucleotides such as ADP, ATP, GTP, UTP (1 mM), while CTP, cAMP, AMP, adenosine (1 mM), ryanodine (0.1-100 mM) and inositol 1,4,5-trisphosphate (1 microM) were not effective. These features of the hepatic microsomal [3H]MBED binding site distinguish it from that of skeletal muscle SR. [3H]MBED, which binds to the different sites which are both sensitive to caffeine, is useful as a probe to investigate the actions of caffeine at the molecular level.
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PMID:The specific binding site of 9-[3H]methyl-7-bromoeudistomin D, a caffeine-like Ca2+ releaser, in liver microsomes in distinct from that in skeletal sarcoplasmic reticulum. 801 Nov 74

We determined whether chronic dosing with phencyclidine (PCP) could affect the in vitro function of liver microsomal enzymes in male Sprague-Dawley rats. PCP chronic dosing of rats (n = 3 per group) for 3 days with 2.5, 10 and 18 mg/kg/day caused a dose-dependent decrease (23, 36 and 53%, respectively) in the ability of the microsomal enzymes to bind covalently PCP metabolites. The 10- and 18-mg/kg/day dosing groups were significantly different from the 3-day saline-infused control group (P < .05). The results from time-dependent dosing studies indicated PCP covalent binding was significantly reduced (P < .05) in rats (n = 3 per group) infused with 18 mg/kg/day of PCP for 1, 2, 3, 4 and 10 days. Subsequently, it returned to near control values in rats infused for 20 days. In parallel with the time-dependent decreases in covalent binding, the concentrations of at least three phase I PCP mono- and dihydroxylated metabolites were also significantly reduced (P < .05) at the earlier time periods of dosing (3 and 10 days), but the rate of their formation returned to near normal values by 20 days of dosing. Total cytochrome P450 content did not differ from the control groups at any of the doses or time points. As dose- and time-dependent decreases in covalent binding suggested a specific metabolic pathway or isoenzyme was affected, we studied the affect on specific isoenzyme pathways. For these studies a series of cytochrome P450 inhibitors were used.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dose- and time-dependent changes in phencyclidine metabolite covalent binding in rats and the possible role of CYP2D1. 851 6

These studies were conducted to determine the effect of hormones on sex-related differences in phencyclidine (PCP) metabolite irreversible binding and to determine the cytochrome P450 isoform(s) involved in this process. Sprague-Dawley male rats were castrated or administered estradiol and Sprague-Dawley female rats were ovarectomized or ovarectomized and given testosterone. Liver microsomal metabolism studies demonstrated that PCP metabolite binding to proteins was significantly altered by testosterone and estrogen administration. Castration of male rats decreased metabolite binding to 57% of sham-operated male levels, and administration of testosterone to ovarectomized female rats increased metabolite binding to 41 % of normal male levels. No metabolite adducts could be detected in microsomes from male rats administered estradiol or from sham-operated females given vehicle. These hormone-induced changes in metabolite binding closely matched the hormone-induced changes in CYP2C11 function and expression in these same microsomes. PCP metabolite irreversible binding to microsomal proteins was highly correlated with CYP2C11 function (as assessed by the formation of 2alpha-OH-testosterone, r = 0.91) and with CYP2C11 expression (as assessed by Western blot analysis, r = 0.95). In addition, an anti-CYP2C11 monoclonal antibody almost completely inhibited PCP metabolite binding (down to 7% of control male values) in an antibody concentration-dependent manner. These data strongly implicate CYP2C11 as an isoform involved in PCP metabolism and the formation and/or binding of a reactive PCP metabolite to microsomal proteins.
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PMID:Phencyclidine metabolite irreversible binding in the rat: gonadal steroid regulation and CYP2C11. 861 33

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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