A novel biologically active seleno-organic compound--V. Inhibition by ebselen (PZ 51) of rat peritoneal neutrophil lipoxygenase.
Suspensions of rat peritoneal PMNLs elicited with glycogen were stimulated by calcium and an ionophore to produce leukotrienes from endogenous arachidonic acid. We investigated the effect of the non-toxic, anti-inflammatory seleno-organic compound, ebselen (PZ 51). When ethanolic extracts of the medium of stimulated cells were analysed by HPLC, a dose-dependent inhibition by ebselen of LTB4 formation with a concomitant decrease of 5-HETE production was found. Half-maximum inhibition was observed at 20 mumoles/l ebselen. Similar findings were obtained after analysis of chloroform extracts of both cells and medium using a different HPLC system. Under these conditions, enhanced 5-HETE formation was associated with reduced production of LTB4 and other di-HETE isomers, when purified glutathione peroxidase + GSH were present. We conclude that the reported GSH peroxidase-like activity of ebselen, catalysing the reduction of 5-HPETE to 5-HETE, can not account for our findings. Therefore, the lipoxygenase reaction itself apparently represents the site of inhibition of LTB4 formation by ebselen.
Safayhi
H
H
Tiegs
G
G
Wendel
A
A
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D005979:Glutathione Peroxidase / Q000494:pharmacology; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D054833:Isoindoles; D007975:Leukotriene B4 / Q000378:metabolism; D016859:Lipoxygenase Inhibitors; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology; D016566:Organoselenium Compounds; D051381:Rats; D011919:Rats, Inbred Strains; D012643:Selenium / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D001393:Azoles; D006893:Hydroxyeicosatetraenoic Acids; D054833:Isoindoles; D016859:Lipoxygenase Inhibitors; D016566:Organoselenium Compounds; D007975:Leukotriene B4; C042986:ebselen; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D005979:Glutathione Peroxidase; D012643:Selenium