Cloricromene inhibits leukotriene formation by human polymorphonuclear leucocytes by suppressing arachidonate release from membrane phospholipids.
Cloricromene, an antithrombotic agent known to inhibit the release of arachidonic acid (AA) in stimulated human platelets, was tested for its effects on arachidonate release and metabolism in human polymorphonuclear leucocytes (PMNs). Cloricromene dose-dependently suppressed the release of leukotriene B4 (LTB4), as assessed by radioimmunoassay, from both isolated PMNs and human whole blood stimulated with the calcium ionophore A23187 or with serum-treated zymosan (STZ). The inhibitory effect was higher when the concentration of the stimulating agent was weaker. Cloricromene also inhibited dose-dependently the liberation of LTB4, LTC4, LTD4 and 5-hydroxy-6,8,11,14-eicosatraenoic acid as assessed by HPLC in the supernantant of A23187-stimulated PMNs. Finally, the drug was able to suppress the release of [3H]AA from purified human PMNs prelabeled with the radioactive fatty acid and stimulated with either A23187 or with STZ. The A23187-induced decrease in the radioactivity of phosphatidylinositol, the phospholipid class mainly involved in AA release in stimulated PMNs, was also inhibited by cloricromene. Cloricromene suppresses leukotriene formation in human PMNs by reducing AA release from membrane phospholipids, possibly through interference with phospholipase A2 activation; this activity may contribute to the leucocyte-inhibitory effects reported previously for cloricromene.
Institute of Internal and Vascular Medicine, University of Perugia, Italy.
P
P
Gresele
E
E
Ribaldi
A M
AM
Mezzasoma
E
E
Quero
M
M
Stasi
M
M
Prosdocimi
G
G
Goracci
G G
GG
Nenci
D016718:Arachidonic Acid / Q000378:metabolism*; D000001:Calcimycin / Q000494:pharmacology; D002866:Chromonar / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis; D007975:Leukotriene B4 / Q000096:biosynthesis*; D008563:Membrane Lipids / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D013189:SRS-A / Q000096:biosynthesis; D015054:Zymosan / Q000494:pharmacology
D006893:Hydroxyeicosatetraenoic Acids; D008563:Membrane Lipids; D010743:Phospholipids; D013189:SRS-A; D007975:Leukotriene B4; D016718:Arachidonic Acid; D000001:Calcimycin; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D015054:Zymosan; C025945:cloricromen; D002866:Chromonar