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Research ArticleArticle

The Nonenzymatic Reactivity of the Acyl-Linked Metabolites of Mefenamic Acid toward Amino and Thiol Functional Group Bionucleophiles

Howard Horng and Leslie Z. Benet
Drug Metabolism and Disposition November 2013, 41 (11) 1923-1933; DOI: https://doi.org/10.1124/dmd.113.053223
Howard Horng
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California
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Leslie Z. Benet
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California
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Abstract

Mefenamic acid (MFA), a carboxylic acid–containing nonsteroidal anti-inflammatory drug, is metabolized into the chemically-reactive MFA-1-O-acyl-glucuronide (MFA-1-O-G), MFA-acyl-adenylate (MFA-AMP), and the MFA-S-acyl-coenzyme A (MFA-CoA), all of which are electrophilic and capable of acylating nucleophilic sites on biomolecules. In this study, we investigate the nonenzymatic ability of each MFA acyl-linked metabolite to transacylate amino and thiol functional groups on the acceptor biomolecules Gly, Tau, l-glutathione (GSH), and N-acetylcysteine (NAC). In vitro incubations with each of the MFA acyl-linked metabolites (1 μM) in buffer under physiologic conditions with Gly, Tau, GSH, or NAC (10 mM) revealed that MFA-CoA was 11.5- and 19.5-fold more reactive than MFA-AMP toward the acylation of cysteine-sulfhydryl groups of GSH and NAC, respectively. However, MFA-AMP was more reactive toward both Gly and Tau, 17.5-fold more reactive toward the N-acyl-amidation of taurine than its corresponding CoA thioester, while MFA-CoA displayed little reactivity toward glycine. Additionally, mefenamic acid-S-acyl-glutathione (MFA-GSH) was 5.6- and 108-fold more reactive toward NAC than MFA-CoA and MFA-AMP, respectively. In comparison with MFA-AMP and MFA-CoA, MFA-1-O-G was not significantly reactive toward all four bionucleophiles. MFA-AMP, MFA-CoA, MFA-1-O-G, MFA-GSH, and mefenamic acid-taurine were also detected in rat in vitro hepatocyte MFA (100 μM) incubations, while mefenamic acid-glycine was not. These results demonstrate that MFA-AMP selectively reacts with the amino functional groups of glycine and lysine nonenzymatically, MFA-CoA selectively reacts nonenzymatically with the thiol functional groups of GSH and NAC, and MFA-GSH reacts with the thiol functional group of GSH nonenzymatically, all of which may potentially elicit an idiosyncratic toxicity in vivo.

Footnotes

    • Received June 21, 2013.
    • Accepted August 23, 2013.
  • This work was supported in part by the National Institutes of Health [Grant GM36633]; and by the University of California, San Francisco, Liver Center Cell Biology Core through the National Institutes of Health [Grant P30 DK026743]. The authors declare no competing financial interests.

  • dx.doi.org/10.1124/dmd.113.053223.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (11)
Drug Metabolism and Disposition
Vol. 41, Issue 11
1 Nov 2013
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Research ArticleArticle

Reactivity of the Acyl-Linked Metabolites of Mefenamic Acid

Howard Horng and Leslie Z. Benet
Drug Metabolism and Disposition November 1, 2013, 41 (11) 1923-1933; DOI: https://doi.org/10.1124/dmd.113.053223

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Research ArticleArticle

Reactivity of the Acyl-Linked Metabolites of Mefenamic Acid

Howard Horng and Leslie Z. Benet
Drug Metabolism and Disposition November 1, 2013, 41 (11) 1923-1933; DOI: https://doi.org/10.1124/dmd.113.053223
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