Modulation of eicosanoid biosynthesis and inhibition of substrate availability for phospholipase A 2 by a modified hexose sugar, amiprilose hydrochloride

Abstract

The modified hexose, sugar, amiprilose HCl [1, 2-O-isopropylinine-3-O-3′-(N′,N′-dimethylamino-n-propyl)- D-glucufuranose hydrochloride], has previously been shown to have antiinflamatory acitivies. The present study assessed whether eicosanoid biosynthesis is regulated by amiprilose HCl adn whether the regulation is influenced at the early stage of arachidonate liberation from the phospholipid by phospholipase A 2 (PLA 2). Secretiion of both prostaglandin E 2 (PGE 2) and leukotriene B 4 (LTB 4) by peritoneal macrophages and neutrophils from amiprilose HCl-treated mice was reduced with neutrophils being slightly more sensitive to the inhibitory effects. Amiprilose HCl was less effective in vitro at inhibiting PGE 2 and LTB 4 secretion that it was in vivo . Amiprilose HCl did not have a direct inhibitory effect on the PLA 2 enzyme or on secretion of the soluble form od PLA 2. In contrast, amiprilose HCl modulated the phospholipid substrate for PLA 2 as there was inhibition of label release from [1- 14C]-oleic acid-labeled substrate source (i) when labeled E. coli substrate for pure PLA 2 had been preincubated with amiprilose HCl, or (ii) when labeled peritoneal cells, which had been preincubated with amiprilose HCl, were used as a substrate source either for pure PLA 2 or for their own PLA 2. Amiprilose HCl was found to bind to peritoneal cells rapidly, but transiently, with maximal binding occurring within 5 min at 37°C. Thus, amiprilose HCl was shown to be inhibitory to secretion of PGE 2 and LTB 4, at least in part, by inhibiting the availability of substrate for PLA 2.