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Toxicological Sciences 53, 40-47 (2000)
Copyright © 2000 by the Society of Toxicology

Activation of Neutrophil Calcium-Dependent and -Independent Phospholipases A2 by Organochlorine Compounds

Patricia K. Tithof*,1, Jesus Olivero{dagger}, Kirsten Ruehle{dagger} and Patricia E. Ganey{dagger}

* College of Veterinary Medicine, The University of Tennessee, 2407 River Drive. Knoxville, Tennessee 37996-4500; and {dagger} Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan

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 (O) 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 O by a mechanism that requires PLA2. Production of Oand 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 O 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 O 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.

Key Words: arachidonic acid; phospholipase A2; organochlorine compounds; neutrophils; superoxide anion; NADPH oxidase.


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