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Research ArticleArticle

SELECTIVE PATHWAYS FOR THE METABOLISM OF PHENCYCLIDINE BY CYTOCHROME P450 2B ENZYMES: IDENTIFICATION OF ELECTROPHILIC METABOLITES, GLUTATHIONE, AND N-ACETYL CYSTEINE ADDUCTS

Mohamad Shebley, Monica I. Jushchyshyn and Paul F. Hollenberg
Drug Metabolism and Disposition March 2006, 34 (3) 375-383; DOI: https://doi.org/10.1124/dmd.105.007047
Mohamad Shebley
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Monica I. Jushchyshyn
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Paul F. Hollenberg
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Abstract

The metabolism of phencyclidine (PCP) has been studied previously in cytochrome P450 (P450)-containing microsomal systems. However, the reactive intermediate(s) that covalently binds to the P450 and leads to inactivation or leaves the active site to modify other proteins has not been identified. In this study two electrophilic intermediates of PCP were identified by mass spectrometry and by trapping with reduced glutathione (GSH) or N-acetyl cysteine (NAC). The tentative structures of these electrophilic intermediates were determined using mass spectrometry. P450s 2B1 and 2B4 formed a metabolite that exhibited an m/z of 240 corresponding to the mass of the 2,3-dihydropyridinium species of PCP or its conjugate base, the 1,2-dihydropyridine. Chemical reduction of the incubation mixture using NaBH4 resulted in the disappearance of the signal at m/z 240, consistent with reduction of a 2,3-dihydropyridinium species. Furthermore, the reactive metabolite trapped by GSH resulted in an adduct exhibiting an m/z of 547, consistent with the mass of the 2,3-dihydropyridinium species of PCP (m/z 240), that has reacted with a molecule of GSH (m/z 308). However, P450 2B6 formed a different reactive intermediate of PCP that was isolated as a GSH adduct exhibiting an m/z of 581 and an NAC adduct with an m/z of 437. Liquid chromatography-tandem mass spectrometry analysis of these adducts suggested that a di-oxygenated iminium metabolite of PCP could be the reactive intermediate formed by P450 2B6 but not by the other 2B isoforms. These data suggest that P450 2B6 favors oxidation pathways for PCP metabolism that are different from those of P450s 2B1 and 2B4.

Footnotes

  • This work was supported in part by National Institutes of Health Grant CA-16954.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.105.007047.

  • ABBREVIATIONS: PCP, phencyclidine; P450, cytochrome P450; MBI, mechanism-based inactivator; DLPC, dilauroyl-l-α-phosphatidylcholine; reductase, NADPH-cytochrome P450 reductase; GSH, glutathione; NAC, N-acetyl cysteine; LC, liquid chromatography; MS, mass spectrometry; ESI, electrospray ionization; MS/MS, tandem mass spectrometry; m/z, mass to charge ratio; TIC, total ion chromatogram; XIC, extracted ion chromatogram; Rt; retention time; MPTP, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; HP, haloperidol, 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-4-piperidinol; TFA, trifluoroacetic acid; HPLC, high-performance liquid chromatography; CID, collision-induced dissociation; 2,3-MPDP+, 1-methyl-4-2,3-dihydropyridinium.

    • Received August 29, 2005.
    • Accepted November 22, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (3)
Drug Metabolism and Disposition
Vol. 34, Issue 3
1 Mar 2006
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SELECTIVE PATHWAYS FOR THE METABOLISM OF PHENCYCLIDINE BY CYTOCHROME P450 2B ENZYMES: IDENTIFICATION OF ELECTROPHILIC METABOLITES, GLUTATHIONE, AND N-ACETYL CYSTEINE ADDUCTS
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Research ArticleArticle

SELECTIVE PATHWAYS FOR THE METABOLISM OF PHENCYCLIDINE BY CYTOCHROME P450 2B ENZYMES: IDENTIFICATION OF ELECTROPHILIC METABOLITES, GLUTATHIONE, AND N-ACETYL CYSTEINE ADDUCTS

Mohamad Shebley, Monica I. Jushchyshyn and Paul F. Hollenberg
Drug Metabolism and Disposition March 1, 2006, 34 (3) 375-383; DOI: https://doi.org/10.1124/dmd.105.007047

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Research ArticleArticle

SELECTIVE PATHWAYS FOR THE METABOLISM OF PHENCYCLIDINE BY CYTOCHROME P450 2B ENZYMES: IDENTIFICATION OF ELECTROPHILIC METABOLITES, GLUTATHIONE, AND N-ACETYL CYSTEINE ADDUCTS

Mohamad Shebley, Monica I. Jushchyshyn and Paul F. Hollenberg
Drug Metabolism and Disposition March 1, 2006, 34 (3) 375-383; DOI: https://doi.org/10.1124/dmd.105.007047
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