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Molecular Pharmacology

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Research ArticleArticle

Nonredox 5-Lipoxygenase Inhibitors Require Glutathione Peroxidase for Efficient Inhibition of 5-Lipoxygenase Activity

Oliver Werz, Dagmar Szellas, Margarete Henseler and Dieter Steinhilber
Molecular Pharmacology August 1998, 54 (2) 445-451; DOI: https://doi.org/10.1124/mol.54.2.445
Oliver Werz
Institute of Pharmaceutical Chemistry, University of Frankfurt, D-60439 Frankfurt, Germany
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Dagmar Szellas
Institute of Pharmaceutical Chemistry, University of Frankfurt, D-60439 Frankfurt, Germany
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Margarete Henseler
Institute of Pharmaceutical Chemistry, University of Frankfurt, D-60439 Frankfurt, Germany
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Dieter Steinhilber
Institute of Pharmaceutical Chemistry, University of Frankfurt, D-60439 Frankfurt, Germany
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Abstract

Nonredox type 5-lipoxygenase (5-LO) inhibitors, such as ZM 230487, its methyl analogue ZD 2138, or the Merck compound L-739,010, suppress cellular leukotriene synthesis of ionophore stimulated granulocytes with IC50 values of about 50 nm. However, in cell homogenates or in preparations of purified enzyme, up to 150-fold higher concentrations are required for similar inhibition of 5-LO activity. This loss of 5-LO inhibition in cell homogenates was reversed by addition of glutathione or dithiothreitol, which increased the inhibitory potency of ZM 230487 or L-739,010 by about 100 to 150-fold so that 5-LO inhibition was comparable with that of intact cells. In the presence of thiols, addition of hydroperoxide [13(S)-HpODE], glutathione-peroxidase inhibition by iodacetate or selenium-deficiency lead to impaired 5-LO inhibition by ZM 230487 in cell homogenates. Moreover, addition of glutathione peroxidase was required for efficient inhibition of purified human 5-LO by ZM 230487. The data suggest that low hydroperoxide concentrations are important for efficient 5-LO inhibition by ZM 230487. The kinetic analysis revealed a noncompetitive inhibition of 5-LO by ZM 230487 at low hydroperoxide levels, whereas it acted as a competitive inhibitor with low affinity under nonreducing conditions in granulocyte homogenates. No such redox-dependent effects were observed with the 5-LO inhibitor BWA4C, the 5-LO activating protein-inhibitor MK-886 or the pentacyclic triterpene acetyl-11-keto-β-boswellic acid. These data suggest that physiological conditions associated with oxidative stress and increased peroxide levels lead to impaired efficacy of nonredox type 5-LO inhibitors like ZM 230487 or L-739,010. This could explain the reported lack of activity of this class of 5-LO inhibitors in chronic inflammatory processes.

Footnotes

    • Received January 21, 1998.
    • Accepted May 8, 1998.
  • Send reprint requests to: Dr. Dieter Steinhilber, Institute of Pharmaceutical Chemistry, University of Frankfurt, Marie-Curie-Str. 9, 60439 Frankfurt, Germany. E-mail:steinhilber{at}em.uni-frankfurt.de

  • This study was supported by Grant Ste 458/3–2from Deutsche Forschungsgemeinschaft (D.S.), and European Union Grant BMH4 CT 96–0229, and a grant from Fonds der Chemischen Industrie.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 54 (2)
Molecular Pharmacology
Vol. 54, Issue 2
1 Aug 1998
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Research ArticleArticle

Nonredox 5-Lipoxygenase Inhibitors Require Glutathione Peroxidase for Efficient Inhibition of 5-Lipoxygenase Activity

Oliver Werz, Dagmar Szellas, Margarete Henseler and Dieter Steinhilber
Molecular Pharmacology August 1, 1998, 54 (2) 445-451; DOI: https://doi.org/10.1124/mol.54.2.445

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Research ArticleArticle

Nonredox 5-Lipoxygenase Inhibitors Require Glutathione Peroxidase for Efficient Inhibition of 5-Lipoxygenase Activity

Oliver Werz, Dagmar Szellas, Margarete Henseler and Dieter Steinhilber
Molecular Pharmacology August 1, 1998, 54 (2) 445-451; DOI: https://doi.org/10.1124/mol.54.2.445
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