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Selective calmodulin antagonists fail to inhibit phorbol ester‐induced superoxide anion release from human neutrophils: effects of antifungal azole derivatives
Author(s) -
HEGEMANN L.,
WEBSTER G. F.,
WOLFF K.
Publication year - 1996
Publication title -
british journal of dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.304
H-Index - 179
eISSN - 1365-2133
pISSN - 0007-0963
DOI - 10.1111/j.1365-2133.1996.tb01147.x
Subject(s) - superoxide , azole , chemistry , calmodulin , phorbol ester , pharmacology , antifungal , phorbol , biochemistry , reactive oxygen species , protein kinase c , medicine , microbiology and biotechnology , signal transduction , biology , enzyme
Summary The ability of antifungal azole derivatives to inhibit superoxide anion release from human leucocytes and the relevance of their documented calmodulin (CaM) antagonism was investigated with respect to anti‐inflammatory drug activity. Econazole, miconazole and clotrimazole were found to inhibit phorbol ester‐induced release of superoxide anions from human polymurphonuclear leucocytes effectively with IC 50 values in the range of 36–162 μmol/1. In contrast, bifonazole and ketoconazole produced minimal or no inhibition, thus suggesting that mechanisms other 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 the release process, whereas W‐7 as a dual CaM/protein kinase C inhibitor induced dose‐dependent inhibition. When tested on protein kinuse C activity in vitro , econazole, miconazole and clotrimazole were inhibitory, but bifonazole and ketoconazole were without significant effect. It is thus concluded that inhibition of superoxide anion release reflects the ability of these drugs to inhibit protein kinase C, but not their potency to antagonize CaM. Given the role of reactive oxygen species in lissue damage hy neutrophils. we propose protein kinase C, rather than CaM, as another potential target of anti‐inflammatory therapy.