Effect of cytochrome P-450 inhibitors econazole, bifonazole and clotrimazole on prostanoid formation

1 The present study was carried out to clarify the effect of the imidazole antimycotics econazole, bifonazole and clotrimazole on prostanoid biosynthe sis. Osteoblast-like MC3T3-E1 cells stimulated by endothelin-1, melittin, i onomycin or arachidonic acid showed diminished prostaglandin E-2 (PGE(2)) p roduction upon pretreatment with econazole. Following pretreatment with bif onazole, stimulation with ionomycin or arachidonic acid also resulted in de creased PGE(2) formation. Clotrimazole inhibited ionomycin but not arachido nic acid stimulated PGE(2) synthesis in MC3T3-E1 cells. 2 The results observed in osteoblast-like UMR-106 cells pretreated with eco nazole, bifonazole or clotrimazole and stimulated by arachidonic acid were similar with the exception of clotrimazole which was a more effective inhib itor of PGE(2) biosynthesis than in MC3T3-E1 cells. 3 Upon treatment with arachidonic acid thromboxane B-2 (TXB2) production in human platelets was abolished completely at concentrations of the three im idazole antimycotics higher than 5 mu M (IC50 < 1 mu M). 4 These data were confirmed by a direct assay using purified ram seminal ve sicle prostaglandin H-2 synthase-1 (PGHS-1), which clearly showed inhibitor y properties of econazole (IC50 4.7+/-2.3 mu M), bifonazole (IC50 9.4 +/- 0 .8 mu M) and clotrimazole (IC50 4.4 +/- 0.6 mu M). 5 Summarizing, these results indicate an inhibitory effect of econazole, bi fonazole and clotrimazole on PGHS-1, varying in its potency dependent on th e cell system used. In addition TXB2 formation is affected at doses even lo wer than those needed to suppress PGE(2) biosynthesis.