Tithof P K, Olivero J, Ruehle K, Ganey P E
College of Veterinary Medicine, The University of Tennessee, Knoxville 37996-4500, USA.
Toxicol Sci. 2000 Jan;53(1):40-7. doi: 10.1093/toxsci/53.1.40.
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.
有机氯农药产生的活性氧物质与这些化合物的毒性和致癌性有关；然而，这些物质刺激氧自由基产生的机制尚不清楚。磷脂酶A2（PLA2）介导的花生四烯酸释放已被证明在暴露于各种生理和药理试剂的中性粒细胞中超氧阴离子（O2-）的产生中起重要作用。因此，进行了研究以确定有机氯农药林丹和狄氏剂是否通过需要PLA2的机制激活中性粒细胞以产生O2-。在用狄氏剂或林丹激活的中性粒细胞中，O2-的产生和3H-AA的释放以相似的动力学和浓度-反应关系增加。在无钙培养基中以及在细胞内钙螯合剂BAPTA-AM存在下，用狄氏剂或林丹刺激的中性粒细胞中可见3H-AA的显著释放，这表明这些物质刺激一种不需要钙激活的PLA2。此外，O2-的产生和3H-AA的释放均被基于机制的钙非依赖性PLA2抑制剂BEL以浓度依赖性方式抑制。这些数据表明，狄氏剂和林丹通过涉及PLA2的机制刺激O2-的产生。然而，3H-AA的释放并未被BEL完全消除，就狄氏剂而言，在无钙的情况下也未完全保留。这表明狄氏剂和林丹激活了不止一种PLA2同工型，并且有一种同工型是钙依赖性的。
