CROCONAZOLE - AN INHIBITOR OF EICOSANOID SYNTHESIS IN A23187-STIMULATED HUMAN POLYMORPHONUCLEAR LEUKOCYTES AND HUMAN WHOLE-BLOOD

The aim of this investigation was to ascertain possible inhibitory eff ects of the antimycotic agent croconazole on eicosanoid biosynthesis, Human polymorphonuclear leukocytes (PMN) and whole blood of healthy do nors were pretreated with croconazole in different concentrations (0.8 -100 mu M) for 5 min followed by the addition of Ca ionophore A23187 ( 10 mu M) and subsequent incubation for 10 min (PMN) and 30 min (whole blood), respectively. Thereupon the eicosanoids were determined by rev ersed-phase high-performance liquid chromatography. Croconazole exhibi ted dose-dependent inhibitory activity on the 5-lipoxygenase (5-LOX) o f neutrophils, The mean half maximum inhibition concentration (IC50) o f croconazole for synthesis of leukotriene B-4 (LTB(4)) and 5-hydroxye icosatetraenoic acid (5-HETE) was determined as 7.8 +/- 1.7 and 7.6 +/ - 0.3 mu M respectively, The mean IC50 value for LTB(4) estimated in w hole blood was distinctly higher (27.0 +/- 3.1 mu M) compared with tha t determined in PMN. Additionally, an inhibitory effect (IC50 9.8 +/- 2.0 mu M) on the production of the cyclooxygenase (COX) product 12-hyd roxyheptadecatrienoic acid (HHT) was demonstrated, whereas the product ion and/or releasing of 12-hydroxyeicosatetraenoic acid (12-HETE) was not attenuated by the azole. Our results in the cell-free 5-LOX system favor a direct inhibitory action of croconazole on 5-LOX, with a rela tively high portion (45-77%) of reversibility. In spite of distinctly lower inhibitory potency compared with reference inhibitors such as no rdihydroguaiaretic acid and indomethacin, croconazole is an effective inhibitor of arachidonic acid metabolism, Our results suggest that cro conazole may be of some benefit in anti-inflammatory therapy.