Ebselen reduces the formation of LTB4 in human and porcine leukocytes by isomerisation to its 5S, 12R-6-trans-isomer

Abstract

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.