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Research ArticleArticle

The Inhibition of Mammalian 15-Lipoxygenases by the Anti-Inflammatory Drug Ebselen: Dual-Type Mechanism Involving Covalent Linkage and Alteration of the Iron Ligand Sphere

Matthias Walther, Hermann-Georg Holzhütter, Ralf Jürgen Kuban, Rainer Wiesner, Jörg Rathmann and Hartmut Kühn
Molecular Pharmacology July 1999, 56 (1) 196-203; DOI: https://doi.org/10.1124/mol.56.1.196
Matthias Walther
Institute of Biochemistry, University Clinics Charité, Humboldt University, Berlin, Germany
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Hermann-Georg Holzhütter
Institute of Biochemistry, University Clinics Charité, Humboldt University, Berlin, Germany
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Ralf Jürgen Kuban
Institute of Biochemistry, University Clinics Charité, Humboldt University, Berlin, Germany
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Rainer Wiesner
Institute of Biochemistry, University Clinics Charité, Humboldt University, Berlin, Germany
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Jörg Rathmann
Institute of Biochemistry, University Clinics Charité, Humboldt University, Berlin, Germany
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Hartmut Kühn
Institute of Biochemistry, University Clinics Charité, Humboldt University, Berlin, Germany
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Abstract

Mammalian lipoxygenases have been implicated in inflammation and atherosclerosis and, thus, lipoxygenase inhibitors may be of pharmacological interest. In cells, lipoxygenases occur in a catalytically silent ground state that requires activation to become active. We found that the seleno-organic drug ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one], which exhibits anti-inflammatory properties, irreversibly inhibited pure rabbit 15-lipoxygenase, with an IC50 in the nM range when preincubated with the enzyme in the absence of fatty acid substrates. Subsequent dialysis, gel filtration, or substrate addition did not restore the enzyme activity, and experiments with [14C]ebselen indicated a covalent linkage of the drug. The presence of sulfhydryl compounds in the incubation mixture prevented both enzyme labeling and inactivation, but we did not see any reactivation when sulfhydryl compounds were added afterward. X-ray absorption studies indicated that ebselen did alter the geometry of the iron ligand sphere, and the data are consistent with an iron complexation by the drug. When fatty acid substrate was present during lipoxygenase-ebselen interaction, the inhibitory potency was strongly reduced and a competitive mode of action was observed. These data suggest that ebselen inactivated the catalytically silent ground-state lipoxygenase irreversibly by covalent linkage and alteration of the iron ligand sphere. In contrast, it functions as a competitive inhibitor of the catalytically active enzyme species. The pharmacological relevance of ebselen as a potential in vivo lipoxygenase inhibitor will be discussed.

Footnotes

    • Received February 8, 1999.
    • Accepted April 12, 1999.
  • Send reprint requests to: Dr. Hartmut Kühn, Institute of Biochemistry, University Clinics Charité, Humboldt University, Hessische Str. 3-4, D-10115 Berlin, Germany. E-mail:hartmut.kuehn{at}rz.hu-berlin.de

  • Financial support was provided by Deutsche Forschungsgemeinschaft (Ku 961/3-1 and 3-2), by the European Commission (BMH4-CT98-3191), and by Daiichi Pharmaceuticals Co., Ltd (Tokyo, Japan).

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 56 (1)
Molecular Pharmacology
Vol. 56, Issue 1
1 Jul 1999
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Research ArticleArticle

The Inhibition of Mammalian 15-Lipoxygenases by the Anti-Inflammatory Drug Ebselen: Dual-Type Mechanism Involving Covalent Linkage and Alteration of the Iron Ligand Sphere

Matthias Walther, Hermann-Georg Holzhütter, Ralf Jürgen Kuban, Rainer Wiesner, Jörg Rathmann and Hartmut Kühn
Molecular Pharmacology July 1, 1999, 56 (1) 196-203; DOI: https://doi.org/10.1124/mol.56.1.196

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Research ArticleArticle

The Inhibition of Mammalian 15-Lipoxygenases by the Anti-Inflammatory Drug Ebselen: Dual-Type Mechanism Involving Covalent Linkage and Alteration of the Iron Ligand Sphere

Matthias Walther, Hermann-Georg Holzhütter, Ralf Jürgen Kuban, Rainer Wiesner, Jörg Rathmann and Hartmut Kühn
Molecular Pharmacology July 1, 1999, 56 (1) 196-203; DOI: https://doi.org/10.1124/mol.56.1.196
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