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Research ArticleArticle

Mechanisms for Covalent Binding of Benoxaprofen Glucuronide to Human Serum Albumin

Studies by Tandem Mass Spectrometry

Y. Qiu, A. L. Burlingame and L. Z. Benet
Drug Metabolism and Disposition March 1998, 26 (3) 246-256;
Y. Qiu
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A. L. Burlingame
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L. Z. Benet
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Studies by Tandem Mass Spectrometry

Abstract

Tandem MS has been used to establish the structure and specific binding sites of covalent protein adducts formed upon incubation of the acyl glucuronide of the propionic acid nonsteroidal anti-inflammatory drug benoxaprofen with human serum albumin in vitro. Benoxaprofen 1-O-β-glucuronide was enzymatically synthesized in vitro and incubated with human serum albumin both in the presence and in the absence of NaCNBH3. The modified human serum albumins were digested with trypsin and separated by HPLC. The modified peptides were detected using HPLC-electrospray MS (with selected-ion monitoring) and were structurally characterized by tandem MS using matrix-assisted laser desorption ionization in both the post-source decay and high-energy collision-induced dissociation modes. These studies established that benoxaprofen glucuronide forms covalent adducts with protein nucleophiles both by nucleophilic displacement of glucuronic acid at the anomeric center and by condensation of the rearranged acyl glucuronic acid isomers with ε-amino functions of lysine residues after acyl migration of the aglycone from the anomeric center. Lys-159 was identified as the major binding site. Thus, we have established that members of the less reactive propionic acid class of acyl glucuronides, such as the glucuronide of benoxaprofen, are also capable of reacting with protein nucleophiles to form covalent adducts analogous to those of tolmetin glucuronide (tolmetin is an acetic acid nonsteroidal anti-inflammatory drug), via the mechanisms previously reported from this laboratory, and that the specific covalent binding site profile appears to be drug dependent.

Footnotes

  • Send reprint requests to: A. L. Burlingame, Department of Pharmaceutical Chemistry, University of California, 513 Parnassus Avenue, San Francisco, CA 94143-0446.

  • Financial support was provided by National Institutes of Health National Center for Research Resources Grant 01614 (to A.L.B.), Grants DK26743 (to A.L.B.) and GM36633 (to L.Z.B.).

  • Abbreviations used are::
    NSAID
    nonsteroidal anti-inflammatory drug
    BG
    benoxaprofen-1-O-β-glucuronide
    SIM
    selected-ion monitoring
    CID
    collision-induced dissociation
    PSD
    post-source decay
    HSA
    human serum albumin
    MALDI
    matrix-assisted laser desorption ionization
    TOF
    time of flight
    TG
    tolmetin glucuronide
    • Received August 6, 1997.
    • Accepted November 12, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 26, Issue 3
1 Mar 1998
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Research ArticleArticle

Mechanisms for Covalent Binding of Benoxaprofen Glucuronide to Human Serum Albumin

Y. Qiu, A. L. Burlingame and L. Z. Benet
Drug Metabolism and Disposition March 1, 1998, 26 (3) 246-256;

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Research ArticleArticle

Mechanisms for Covalent Binding of Benoxaprofen Glucuronide to Human Serum Albumin

Y. Qiu, A. L. Burlingame and L. Z. Benet
Drug Metabolism and Disposition March 1, 1998, 26 (3) 246-256;
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