Mechanism of action of the nonlipophilic antiallergic drug eclazolast (REV 2871) in the inhibition of mediator release in a mast cell model.
OBJECTIVE
In this study, we compared eclazolast with other lipophilic antiallergic drugs, relating to effects on signal transduction pathways, leading to inhibition of exocytosis in a rat basophilic leukemia cell (RBL-2H3).


METHODS
Effects of the drugs on mediator release (beta-hexosaminidase, arachidonic acid metabolites) after Fc(epsilon)RI activation in RBL-2H3 cell were quantified. Furthermore, effects of the drugs on cellular signalling (Ca2+ influx, intracellular Ca2+ concentration, inositol 1,4,5-trisphosphate (IP3) concentration) were assayed. Effects of the drugs on bilayer and cell membranes have been recorded.


RESULTS
It is shown that eclazolast down-regulates IP3 levels. In contrast to lipophilic drugs, eclazolast does not affect artificial bilayers and erythrocyte membranes, and there is no effect on thapsigargin induced Ca2+ influx. The effect of eclazolast was highly dependent on the antigen concentration with which the cells were triggered.


CONCLUSIONS
The mechanism of action of eclazolast is deviant from lipophilic antiallergic agents. It inhibits exocytosis by intracellularly affecting only direct Fc(epsilon)RI linked processes and not through inhibition of Ca2+ influx channels, as found for membrane disturbing lipophilic drugs.
Fischer
M J
MJ
Department of Medicinal Chemistry, Utrecht Institute for Pharmaceutical Sciences, Faculty of Pharmacy, Utrecht University, The Netherlands. M.J.E.Fischer@pharm.uu.nl
de Mol
N J
NJ
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D002460:Cell Line; D004912:Erythrocytes / Q000187:drug effects; D005089:Exocytosis / Q000187:drug effects; D005353:Fibronectins / Q000378:metabolism; D006461:Hemolysis / Q000187:drug effects; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D018836:Inflammation Mediators / Q000378:metabolism*; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis; D008051:Lipid Bilayers; D008081:Liposomes; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism*; D010080:Oxazoles / Q000494:pharmacology*; D051381:Rats; D011961:Receptors, Fc / Q000187:drug effects; D017455:Receptors, IgE / Q000187:drug effects; D018047:Receptors, Purinergic P1 / Q000187:drug effects; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
D015220:Calcium Channels; D005353:Fibronectins; D006634:Histamine H1 Antagonists; D007202:Indicators and Reagents; D018836:Inflammation Mediators; D008051:Lipid Bilayers; D008081:Liposomes; D010080:Oxazoles; D011961:Receptors, Fc; D017455:Receptors, IgE; D018047:Receptors, Purinergic P1; D016718:Arachidonic Acid; C049843:2-ethoxyethyl 5-chlorobenzoxazole-2-carboxylate; D015544:Inositol 1,4,5-Trisphosphate; D001619:beta-N-Acetylhexosaminidases