Modulation of eicosanoid biosynthesis and inhibition of substrate availability for phospholipase A2 by a modified hexose sugar, amiprilose hydrochloride.
The modified hexose sugar, amiprilose HCl [1,2-O-isopropylinine-3-O-3'-(N',N'-dimethylamino-n-propyl)-D-g lucufuranose hydrochloride], has previously been shown to have antiinflammatory activities. The present study assessed whether eicosanoid biosynthesis is regulated by amiprilose HCl and whether the regulation is influenced at the early stage of arachidonate liberation from the phospholipid by phospholipase A2 (PLA2). Secretion of both prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) 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 PGE2 and LTB4 secretion that it was in vivo. Amiprilose HCl did not have a direct inhibitory effect on the PLA2 enzyme or on secretion of the soluble form of PLA2. In contrast, amiprilose HCl modulated the phospholipid substrate for PLA2 as there was inhibition of label release from [1-14C]-oleic acid-labeled substrate source (i) when labeled E. coli substrate for pure PLA2 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 PLA2 or for their own PLA2. Amiprilose HCl was found to bind to peritoneal cells rapidly, but transiently, with maximal binding occurring within 5 min at 37 degrees C. Thus, amiprilose HCl was shown to be inhibitory to secretion of PGE2 and LTB4, at least in part, by inhibiting the availability of substrate for PLA2.
Young
M R
MR
Hines V.A. Hospital, IL 60141.
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001682:Biological Availability; D002478:Cells, Cultured; D015232:Dinoprostone / Q000378:metabolism; D015777:Eicosanoids / Q000096:biosynthesis*; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism; D005944:Glucosamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007975:Leukotriene B4 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010529:Peritoneal Cavity / Q000166:cytology; D010740:Phospholipases / Q000378:metabolism*; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D010743:Phospholipids / Q000378:metabolism; D011863:Radioimmunoassay; D012266:Ribose / Q000031:analogs & derivatives
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015777:Eicosanoids; D010743:Phospholipids; D007975:Leukotriene B4; D012266:Ribose; D010740:Phospholipases; D010741:Phospholipases A; D054467:Phospholipases A2; D015232:Dinoprostone; D005944:Glucosamine; C018424:amiprilose