メシル酸ガベキセート（ＧＭ）およびその分解産物（ＧＣＡ）・分解類似物（ＰＨＢＡＭＥ）の好中球ＮＡＤＰＨ ｏｘｉｄａｓｅ ｓｙｓｔｅｍに与える影響

Abstract

We investigated the mechanism by which the synthetic protease inhibitor, gabexate mesilate, inhibits the production of the superoxide anion by human neutrophils and its active site of gabexate mesilate. We found that gabexate mesilate suppressed lucigenin-dependent chemiluminescence in intact neutrophils activated with PMA, but its degraded analog, methylparaben and another degraded product, guanidinocaproic acid did not.Dose-dependent suppression of SOD-inhabitable cytochrome c reduction was also detected in gabexate mesilate-treated neutrophils activated with phorbol ester. Gabexate mesilate slightly scavenged the superoxide anion in the pyrogallol assay. Gabexate mesilate also inhibited superoxide anion production in a dose-dependent manner in a cell-free oxidase-activating system. Translocation of the cytosolic respiratory burst oxidase components, the 47- and 65-kDa proteins, to membranes was suppressed by gabexate mesilate in intact cells stimulated with phorbol ester. Gabexate mesilate also reduced arachidonic acid-induced translocation of the components to the membrane fraction in the cell-free system.These results demonstrate that gabexate mesilate suppresses superoxide anion production by inhibiting the translocation of the 47- and 65-kDa proteins to the plasma membrane and suppression of superoxide anion production requires whole molecule of gabexate mesilate.