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Research ArticleArticle

Activated Sulfonamides are Cleaved by Glutathione-S-Transferases

Kenneth A. Koeplinger, Zhiyang Zhao, Tillie Peterson, Joseph W. Leone, Francis S. Schwende, Robert L. Heinrikson and Alfredo G. Tomasselli
Drug Metabolism and Disposition September 1999, 27 (9) 986-991;
Kenneth A. Koeplinger
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Zhiyang Zhao
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Tillie Peterson
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Joseph W. Leone
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Francis S. Schwende
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Robert L. Heinrikson
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Alfredo G. Tomasselli
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Abstract

In preclinical pharmacokinetic studies and in in vitro rat, dog, and human primary hepatocyte incubations, the sulfonamide (-NH-SO2-) bond of a potent inhibitor of the HIV-1 protease containing the p-cyanopyridinyl moiety (PNU-109112), undergoes metabolic cleavage to form the corresponding amine metabolite (PNU-143070). Strikingly, a compound, PNU-140690, obtained by substituting the cyanopyridinyl group of PNU-109112 with a trifluoropyridinyl moiety, was stable under the same in vivo and in vitro conditions used for PNU-109112. The apparent “sulfonamidase activity” present in liver was localized to the cytosolic fraction and shown to be an enzyme-mediated reaction requiring reduced glutathione (GSH). The enzyme responsible was purified in a single step on a GSH immobilized gel and was identified as glutathione-S-transferase (GST) by sequence analysis of peptides obtained by tryptic digestion of the purified protein. Moreover, a mixture of GST isoenzymes purified from rat liver, and three recombinant human GST isoforms, A1–1, M1–1, and P1–1, were active toward PNU-109112 sulfonamide cleavage; the three isoforms exhibited differential rates of PNU-109112 cleavage, demonstrating isoenzyme selectivity.

Footnotes

  • Send reprint requests to: Dr. A.G. Tomasselli, 7240–267-118, 301 Henrietta St., Kalamazoo, MI 49007-4940. E-mail:alfredo.tomasselli{at}am.pnu.com

  • ↵1 Present address: Drug Metabolism, Central Research, Pfizer, Inc., Groton, CT 06340.

  • Abbreviations used are::
    GST
    glutathione-S-transferase
    DMSO
    dimethyl sulfoxide
    PMSF
    phenylmethylsulfonyl fluoride
    DTT
    (−)-1,4-dithio-l-threitol
    PCMB
    parachloromercuriobenzoate
    β-mercaptoethanol
    2-mercaptoethanol
    ESI
    electrospray ionization
    MS
    mass spectrometry
    TFA
    trifluoroacetic acid
    • Received February 11, 1999.
    • Accepted May 20, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 27 (9)
Drug Metabolism and Disposition
Vol. 27, Issue 9
1 Sep 1999
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Research ArticleArticle

Activated Sulfonamides are Cleaved by Glutathione-S-Transferases

Kenneth A. Koeplinger, Zhiyang Zhao, Tillie Peterson, Joseph W. Leone, Francis S. Schwende, Robert L. Heinrikson and Alfredo G. Tomasselli
Drug Metabolism and Disposition September 1, 1999, 27 (9) 986-991;

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Research ArticleArticle

Activated Sulfonamides are Cleaved by Glutathione-S-Transferases

Kenneth A. Koeplinger, Zhiyang Zhao, Tillie Peterson, Joseph W. Leone, Francis S. Schwende, Robert L. Heinrikson and Alfredo G. Tomasselli
Drug Metabolism and Disposition September 1, 1999, 27 (9) 986-991;
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