RT Journal Article
SR Electronic
T1 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
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 735
OP 745
VO 294
IS 2
A1 Abdul E. Mutlib
A1 John Shockcor
A1 Robert Espina
A1 Nilsa Graciani
A1 Alicia Du
A1 Liang-Shang Gan
YR 2000
UL http://jpet.aspetjournals.org/content/294/2/735.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics