Ebselen reduces the formation of LTB4 in human and porcine leukocytes by isomerisation to its 5S, 12R-6-trans-isomer.
Ebselen, a new organoselenium compound with pronounced anti-inflammatory properties, selectively inhibits the formation of leukotriene B4 in human and porcine leukocytes with half-maximal inhibition at 4.0 and 2.7 mumol/1, respectively. The underlying mechanism was found to be a cis-trans-isomerisation of leukotriene B4 to the 5S, 12R-6-trans-isomer. 5-Hydroxy-eicosatetraenoic acid was also isomerised to the 8-trans-isomer. At higher concentrations, ebselen induces a dose-dependent decrease in the sum of total 5-lipoxygenase products with half-maximal inhibition at 30 mumol/1. Additionally, the effects of ebselen on human platelet 12-lipoxygenase and cyclooxygenase were investigated. Human platelet 12-lipoxygenase and cyclooxygenase were inhibited in a dose dependent manner with half-maximal inhibition at 20 mumol/1 and 5 mumol/1, respectively. We suggest that suppression of leukotriene B4-formation by isomerisation to a biologically inactive compound represents a promising approach to the therapy of inflammation.
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D001393:Azoles / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000032:analysis; D054833:Isoindoles; D007536:Isomerism; D007962:Leukocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D007975:Leukotriene B4 / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D016566:Organoselenium Compounds; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012643:Selenium / Q000494:pharmacology*; D013552:Swine
D001095:Arachidonic Acids; D001393:Azoles; D006893:Hydroxyeicosatetraenoic Acids; D054833:Isoindoles; D016566:Organoselenium Compounds; D007975:Leukotriene B4; D016718:Arachidonic Acid; C042986:ebselen; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D001092:Arachidonate 12-Lipoxygenase; D001094:Arachidonate 5-Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D012643:Selenium