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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Disposition of Glutathione Conjugates in Rats by a Novel Glutamic Acid Pathway: Characterization of Unique Peptide Conjugates by Liquid Chromatography/Mass Spectrometry and Liquid Chromatography/NMR

Abdul E. Mutlib, John Shockcor, Robert Espina, Nilsa Graciani, Alicia Du and Liang-Shang Gan
Journal of Pharmacology and Experimental Therapeutics August 2000, 294 (2) 735-745;
Abdul E. Mutlib
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John Shockcor
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Robert Espina
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Nilsa Graciani
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Alicia Du
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Liang-Shang Gan
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Abstract

With the advent of liquid chromatography/mass spectrometry and liquid chromatography/NMR, it has become easier to characterize metabolites that were once difficult to isolate and identify. These techniques have enabled us to uncover the existence of an alternate pathway for the disposition of glutathione adducts of several structurally diverse compounds. Studies were carried out using acetaminophen as a model compound to investigate the role of the glutamic acid pathway in disposition of the glutathione adducts. Although the mercapturic acid pathway was the major route of degradation of the glutathione adducts, it was found that the conjugation of the glutathione, cysteinylglycine, and cysteine adducts of acetaminophen with the γ-carboxylic acid of the glutamic acid was both interesting and novel. The coupling of the glutathione adduct and the products from the mercapturic acid pathway with the glutamic acid led to unusual peptide conjugates. The natures of these adducts were confirmed unequivocally by comparisons with synthetic standards. This pathway (addition of glutamic acids) led to larger peptides, in contrast to the mercapturic acid pathway, in which the glutathione adducts are broken down to smaller molecules. The enzyme responsible for the addition of glutamic acid to the different elements of the mercapturic acid pathway is currently unknown. It is postulated that the γ-carboxylic acid is activated (perhaps by ATP) before enzymatic addition to the α-amino group of cysteine or glutamate takes place. The discovery of these peptide conjugates of acetaminophen represents a novel disposition of glutathione adducts of compounds. The formation of such conjugates may represent yet another pathway by which drugs could produce covalent binding via their reactive intermediates.

Footnotes

  • Send reprint requests to: Dr. A. E. Mutlib, Drug Metabolism and Pharmacokinetics Section, DuPont Pharmaceuticals Company, P.O. Box 30, 1094 Elkton Rd., Newark, DE 19714-0030. E-mail:abdul.mutlib{at}dupontpharma.com

  • Abbreviations:
    GSH
    glutathione
    LC
    liquid chromatography
    FMOC
    N-α-fluorenylmethoxycarbonyl
    MS
    mass spectrometry
    SPE
    solid phase extraction
    COSY
    correlated spectroscopy
    TOCSY
    total correlated spectroscopy
    HMBC
    heteronuclear multiple bond coherence
    HSQC
    heteronuclear single quantum coherence
    • Received November 16, 1999.
    • Accepted April 26, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 294 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 294, Issue 2
1 Aug 2000
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Disposition of Glutathione Conjugates in Rats by a Novel Glutamic Acid Pathway: Characterization of Unique Peptide Conjugates by Liquid Chromatography/Mass Spectrometry and Liquid Chromatography/NMR

Abdul E. Mutlib, John Shockcor, Robert Espina, Nilsa Graciani, Alicia Du and Liang-Shang Gan
Journal of Pharmacology and Experimental Therapeutics August 1, 2000, 294 (2) 735-745;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Disposition of Glutathione Conjugates in Rats by a Novel Glutamic Acid Pathway: Characterization of Unique Peptide Conjugates by Liquid Chromatography/Mass Spectrometry and Liquid Chromatography/NMR

Abdul E. Mutlib, John Shockcor, Robert Espina, Nilsa Graciani, Alicia Du and Liang-Shang Gan
Journal of Pharmacology and Experimental Therapeutics August 1, 2000, 294 (2) 735-745;
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