SELECTIVE CALMODULIN ANTAGONISTS FAIL TO INHIBIT PHORBOL ESTER-INDUCED SUPEROXIDE ANION RELEASE FROM HUMAN NEUTROPHILS - EFFECTS OF ANTIFUNGAL AZOLE DERIVATIVES

The ability of antifungal azole derivatives to inhibit superoxide anio n release from human leucocytes and the relevance of their documented calmodulin (CaM) antagonism was investigated with respect to anti-infl ammatory drug activity, Econazole, miconazole and clotrimazole were fo und to inhibit phorbol ester-induced release of superoxide anions from human polymorphonuclear leucocytes effectively with IC50 values in th e range of 36-162 mu mol/l. In contrast, bifonazole and ketoconazole p roduced minimal or no inhibition, thus suggesting that mechanisms othe r than inhibition of superoxide anion release may largely account for their clinical activity in inflammatory skin disorders. The selective CaM antagonist J-8, which was used as a reference, failed to inhibit t he release process, whereas W-7 as a dual CaM/protein kinase C inhibit or induced dose-dependent inhibition, When tested on protein kinase C activity in vitro, econazole, miconazole and clotrimazole were inhibit ory, but bifonazole and ketoconazole were without significant effect. It is thus concluded that inhibition of superoxide anion release refle cts the ability of these drugs to inhibit protein kinase C, but not th eir potency to antagonize CaM, Given the role of reactive oxygen speci es in tissue damage by neutrophils, we propose protein kinase C, rathe r than CaM, as another potential target of anti-inflammatory therapy.