Differential inhibition of human secretory and cytosolic phospholipase A

The roles and relative contributions of secretory and cytosolic phospholipases A in physiology and pathology are not precisely known. In a search for differential inhibitors of these enzymes, which could serve as tools to clarify this issue, we evaluated the potencies of reference compounds and three series of new compounds, viz. substrate analogues, 1,2-amino alcohols and enolized β-tricarbonyl derivatives, as inhibitors of secretory phospholipase A from human polymorphonuclear leukocytes (sPLA) and of cytosolic phospholipase A from human U937 cells (cPLA). With few exceptions, the compounds selected are potent inhibitors of sPLA with IC values (concentration inhibiting 50%) in the low micromolar range. Inhibition of cPLA was only observed with some phosphate-free substrate analogues, with 1,2-amino alcohols and two of seven reference compounds. These results suggest that inhibition of secretory and of cytosolic phospholipases A are independent effects. Several inhibitors could be identified with a marked selectivity for sPLA. © 1993 Birkhäuser Verlag.