Strong inhibition of mammalian lipoxygenases by the antiinflammatory seleno-organic compound ebselen in the absence of glutathione.
Both human recombinant 5-lipoxygenase (EC 1.13.11.34) and 15-lipoxygenase (EC 1.13.11.33, mammalian enzyme) purified from rabbit reticulocytes were inhibited in the absence of glutathione (GSH) by submicromolar concentrations of the seleno-organic compound ebselen. These concentrations were comparable to those of the enzymes. Soybean lipoxygenase-1 (EC 1.13.11.33, plant enzyme) was not inhibited, whereas prostaglandin endoperoxide synthase-1 (EC 1.14.99.1) was inhibited only at much higher concentrations of ebselen (IC50 = 37.7 +/- 4.3 microM). The action of ebselen on reticulocyte 15-lipoxygenase (IC50 = 0.17 +/- 0.01 microM) was studied in detail. Inhibition occurred instantaneously and appeared to be reversible and was largely abolished by a 20-fold molar excess of GSH over ebselen. In the presence of 1 mM GSH 50% inhibition was observed only at ebselen concentrations as high as 234 +/- 27 microM. 13S-hydroperoxy-9Z, 11E-octadecadienoic acid, the lipoxygenase product formed from linoleic acid, augmented the inhibitory effect at low concentrations and caused a partial reversal at high concentrations. A variety of derivatives or structural analogues of ebselen were also tested and proved to be either inactive or weaker inhibitors of 15-lipoxygenase. We have concluded that the potent inhibition of 15-lipoxygenase by ebselen is due neither to GSH peroxidase-like activity nor to lowering of the hydroperoxide tone. The pharmacological implications of these unique characteristics of the action of ebselen on lipoxygenases are then discussed.
Schewe
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C
University Clinics Charité, Institute of Biochemistry, Humboldt University of Berlin, Germany.
Schewe
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T
Wendel
A
A
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001393:Azoles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000378:metabolism / Q000494:pharmacology; D005978:Glutathione / Q000494:pharmacology*; D006801:Humans; D054833:Isoindoles; D008041:Linoleic Acids / Q000494:pharmacology; D008054:Lipid Peroxides; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D016566:Organoselenium Compounds / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011817:Rabbits
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001393:Azoles; D016861:Cyclooxygenase Inhibitors; D054833:Isoindoles; D008041:Linoleic Acids; D008054:Lipid Peroxides; D016859:Lipoxygenase Inhibitors; D016566:Organoselenium Compounds; C038649:13-hydroperoxy-9,11-octadecadienoic acid; C042986:ebselen; D005978:Glutathione