Activation of neutrophil calcium-dependent and -independent phospholipasesA(2) by organochlorine compounds

The production of reactive oxygen species by organochlorine pesticides has been implicated in the toxicity and carcinogenicity of these compounds; how ever, the mechanism by which these agents stimulate the production of oxyge n radicals is unknown. Phospholipase A(2) (PLA(2))-mediated release of arac hidonic acid has been shown to play an essential role in superoxide anion ( O-2(-)) production in neutrophils exposed to various physiologic and pharma cologic agents. Therefore, studies were performed to determine if the organ ochlorine pesticides, lindane and dieldrin, activate neutrophils to produce O-2(-) by a mechanism that requires PLA(2). Production of O-2(-) and H-3-A A release increased with similar kinetics and concentration-response relati ons in neutrophils activated with either dieldrin or lindane. Significant r elease of H-3-AA was seen in neutrophils stimulated with dieldrin or lindan e in calcium-free medium and in the presence of the intracellular calcium c helator BAPTA-AM, suggesting that these agents stimulate a PLA(2) that does not require calcium for activation. In addition, both O-2(-) production an d H-3-AA release were inhibited in a concentration-dependent manner by EEL, a mechanism-based inhibitor of calcium-independent PLA(2), These data sugg est that dieldrin and lindane stimulate O-2(-) production by a mechanism th at involves PLA(2). However, release of H-3-AA was not abrogated completely by EEL nor, in the case of dieldrin, preserved entirely in the absence of calcium. This suggests that more than one isoform of PLA(2) is activated by dieldrin and by lindane, and that one isoform is calcium-dependent.