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Effects of pyrrophenone, an inhibitor of group IVA phospholipase A 2 , on eicosanoid and PAF biosynthesis in human neutrophils
Author(s) -
Flamand N,
Picard S,
Lemieux L,
Pouliot M,
Bourgoin S G,
Borgeat P
Publication year - 2006
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0706879
Subject(s) - biosynthesis , arachidonic acid , eicosanoid , phospholipase a2 , platelet activating factor , biochemistry , chemistry , lipid signaling , phospholipase a , pharmacology , biology , enzyme , endocrinology
Background and Purpose: The biosynthesis of leukotrienes (LT) and platelet‐activating factor (PAF) involves the release of their respective precursors, arachidonic acid (AA) and lyso‐PAF by the group IVA PLA 2 (cPLA 2 α). This paper aims at characterizing the inhibitory properties of the cPLA 2 α inhibitor pyrrophenone on eicosanoids and PAF in human neutrophils (PMN). Experimental Approach: Freshly isolated human PMN were activated with physiological and pharmacological agents (fMLP, PAF, exogenous AA, A23187 and thapsigargin) in presence and absence of the cPLA 2 α inhibitor pyrrophenone and biosynthesis of LT, PAF, and PGE 2 was measured. Key Results: Pyrrophenone potently inhibited LT, PGE 2 and PAF biosynthesis in PMN with IC 50 s in the range of 1–20 nM. These inhibitory effects of pyrrophenone were specific (the consequence of substrate deprivation), as shown by the reversal of inhibition by exogenous AA and lyso‐PAF. Comparative assessment of pyrrophenone, methyl‐arachidonoyl‐fluoro‐phosphonate (MAFP) and arachidonoyl‐trifluoromethylketone (AACOCF 3 ) demonstrated that pyrrophenone was more specific and 100‐fold more potent than MAFP and AACOCF 3 for the inhibition of LT biosynthesis in A23187‐activated PMN. The inhibitory effect of pyrrophenone on LT biosynthesis was reversible as LT biosynthesis was recovered when pyrrophenone‐treated PMN were washed with autologous plasma. No alteration of phospholipase D (PLD) activity in fMLP‐activated PMN was observed with up to 10 μM pyrrophenone, suggesting that the cPLA 2 α inhibitor does not directly inhibit PLD. Conclusions and Implications: Pyrrophenone is a more potent and specific cPLA 2 α inhibitor than MAFP and AACOCF 3 and represents an excellent pharmacological tool to investigate the biosynthesis and the biological roles of eicosanoids and PAF. British Journal of Pharmacology (2006) 149 , 385–392. doi: 10.1038/sj.bjp.0706879