Activation of neutrophil calcium-dependent and -independent phospholipases A2 by organochlorine compounds.
The production of reactive oxygen species by organochlorine pesticides has been implicated in the toxicity and carcinogenicity of these compounds; however, the mechanism by which these agents stimulate the production of oxygen radicals is unknown. Phospholipase A2 (PLA2)-mediated release of arachidonic acid has been shown to play an essential role in superoxide anion (O2-) production in neutrophils exposed to various physiologic and pharmacologic agents. Therefore, studies were performed to determine if the organochlorine pesticides, lindane and dieldrin, activate neutrophils to produce O2- by a mechanism that requires PLA2. Production of O2- and 3H-AA release increased with similar kinetics and concentration-response relations in neutrophils activated with either dieldrin or lindane. Significant release of 3H-AA was seen in neutrophils stimulated with dieldrin or lindane in calcium-free medium and in the presence of the intracellular calcium chelator BAPTA-AM, suggesting that these agents stimulate a PLA2 that does not require calcium for activation. In addition, both O2- production and 3H-AA release were inhibited in a concentration-dependent manner by BEL, a mechanism-based inhibitor of calcium-independent PLA2. These data suggest that dieldrin and lindane stimulate O2- production by a mechanism that involves PLA2. However, release of 3H-AA was not abrogated completely by BEL nor, in the case of dieldrin, preserved entirely in the absence of calcium. This suggests that more than one isoform of PLA2 is activated by dieldrin and by lindane, and that one isoform is calcium-dependent.
Tithof
P K
PK
College of Veterinary Medicine, The University of Tennessee, Knoxville 37996-4500, USA. ptithof@utkux.utcc.utk.edu
Olivero
J
J
Ruehle
K
K
Ganey
P E
PE
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002614:Chelating Agents / Q000494:pharmacology; D004026:Dieldrin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D054522:Group VI Phospholipases A2; D001556:Hexachlorocyclohexane / Q000494:pharmacology*; D007306:Insecticides / Q000494:pharmacology*; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology; D018375:Neutrophil Activation / Q000187:drug effects*; D009504:Neutrophils / Q000201:enzymology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054467:Phospholipases A2; D011753:Pyrones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism
D002614:Chelating Agents; D007306:Insecticides; D009281:Naphthalenes; D010726:Phosphodiesterase Inhibitors; D011753:Pyrones; D013481:Superoxides; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D016718:Arachidonic Acid; D004533:Egtazic Acid; D001556:Hexachlorocyclohexane; C068314:6-(bromomethylene)tetrahydro-3-(1-naphthaleneyl)-2H-pyran-2-one; D010741:Phospholipases A; D054522:Group VI Phospholipases A2; D054467:Phospholipases A2; D004026:Dieldrin; D002118:Calcium