Strong inhibition of mammalian lipoxygenases by the antiinflammatory seleno-organic compound ebselen in the absence of glutathione

Biochem Pharmacol. 1994 Jul 5;48(1):65-74. doi: 10.1016/0006-2952(94)90224-0.

Abstract

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.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / antagonists & inhibitors
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Azoles / antagonists & inhibitors
  • Azoles / pharmacology*
  • Cyclooxygenase Inhibitors / metabolism
  • Cyclooxygenase Inhibitors / pharmacology
  • Glutathione / pharmacology*
  • Humans
  • Linoleic Acids / pharmacology
  • Lipid Peroxides*
  • Lipoxygenase Inhibitors / pharmacology*
  • Organoselenium Compounds / antagonists & inhibitors
  • Organoselenium Compounds / pharmacology*
  • Rabbits

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Azoles
  • Cyclooxygenase Inhibitors
  • Linoleic Acids
  • Lipid Peroxides
  • Lipoxygenase Inhibitors
  • Organoselenium Compounds
  • 13-hydroperoxy-9,11-octadecadienoic acid
  • ebselen
  • Glutathione