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Research ArticleArticle

Glutathione S-Transferase Metabolism of the Antineoplastic Pentafluorophenylsulfonamide in Tissue Culture and Mice

Walter P. Frankmoelle, Julio C. Medina, Bei Shan, Mathew R. Narbut and Holger Beckmann
Drug Metabolism and Disposition August 2000, 28 (8) 951-958;
Walter P. Frankmoelle
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Julio C. Medina
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Bei Shan
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Mathew R. Narbut
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Holger Beckmann
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Abstract

The microtubule disrupting agent 2-fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene (T138067) binds covalently and selectively to β-tubulin and has been shown to evade drug-efflux pumps that confer multidrug resistance to other antimitotic drugs that are used in cancer chemotherapy (Shan et al., 1999). In addition to these resistance mechanisms, eukaryotic cells have developed other protection mechanisms that involve enzymes that modify electrophilic xenobiotics. To determine whether T138067 is a substrate for such enzymatic detoxification pathways, a metabolism study was initiated. GSH conjugation was shown to play a major role in T138067 metabolism. T138067-GSH conjugates were isolated from the culture media of T138067-treated cells and the bile of mice treated i.v. with T138067. The major T138067-GSH degradation products were also isolated from these sources. 19F NMR studies of the metabolites showed that metabolic conversions occurred through substitution of the para fluorine atom in the pentafluorophenyl ring of T138067. The T138067-GSH conjugate was also isolated from T138067 incubation buffer that had been exposed to mouse, rat, dog, or human liver slices, suggesting that this mechanism is not species-specific. All three human glutathioneS-transferases (α, μ, and π), which are expressed in a wide variety of tissues including human tumors, were shown to metabolize T138067 effectively in vitro. The combined data show that T138067 is being metabolized, in vitro and in vivo, predominantly via a glutathione S-transferase-mediated metabolic pathway.

Footnotes

  • Send reprint requests to: Dr. Holger Beckmann, Tularik Inc., Two Corporate Drive, South San Francisco, CA 94080. E-mail:beckmann{at}tularik.com

  • Abbreviations used are::
    T138067
    2-fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene
    ES
    electrospray
    GST
    glutathione S-transferase
    MDR
    multidrug resistant
    MS
    mass spectrometry
    T138068
    1-methoxy-4-pentafluorophenylsulfonamidobenzene
    RT
    retention time
    • Received December 8, 1999.
    • Accepted April 17, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (8)
Drug Metabolism and Disposition
Vol. 28, Issue 8
1 Aug 2000
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Research ArticleArticle

Glutathione S-Transferase Metabolism of the Antineoplastic Pentafluorophenylsulfonamide in Tissue Culture and Mice

Walter P. Frankmoelle, Julio C. Medina, Bei Shan, Mathew R. Narbut and Holger Beckmann
Drug Metabolism and Disposition August 1, 2000, 28 (8) 951-958;

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Research ArticleArticle

Glutathione S-Transferase Metabolism of the Antineoplastic Pentafluorophenylsulfonamide in Tissue Culture and Mice

Walter P. Frankmoelle, Julio C. Medina, Bei Shan, Mathew R. Narbut and Holger Beckmann
Drug Metabolism and Disposition August 1, 2000, 28 (8) 951-958;
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