Kousba A A, Poet T S, Timchalk Charles
Battelle, Pacific Northwest Division, 902 Battelle Blvd., PO Box 999, Richland, WA 99352, USA.
Toxicology. 2003 Jun 30;188(2-3):219-32. doi: 10.1016/s0300-483x(03)00090-8.
The primary mechanism of action for organophosphorus (OP) insecticides such as chlorpyrifos (CPF) involves the inhibition of acetylcholinesterase (AChE) by their active oxon metabolites resulting in a wide range of neurotoxic effects. These oxons also inhibit other cholinesterases (ChE) such as butyrylcholinesterase (BuChE), which represents a detoxification mechanism and a potential biomarker for OP insecticide exposure/response. Salivary biomonitoring has recently been explored as a practical method for examination of chemical exposure, however, there are few studies exploring the use of saliva for OP insecticides. To evaluate the use of salivary ChE as a biological monitor for OP insecticide exposure, a modified Ellman assay in conjunction with a pharmacodynamic model was used to characterize salivary ChE in adult male Sprague-Dawley rats. Comparison of rat saliva, brain, and plasma ChE activity in the presence of selective inhibitors of AChE and BuChE (BW284C51 and iso-OMPA, respectively) with different ChE substrates indicated that rat salivary ChE activity is primarily associated with BuChE (>95%). Further characterization of rat salivary BuChE kinetics yielded an average total BuChE active site concentration of 1.20+/-0.13 fmol ml(-1) saliva, an average reactivation rate constant (Kr) of 0.070+/-0.008 h(-1), and an inhibitory rate constant (Ki) of approximately 9 nM(-1) h(-1). The pharmacodynamic model successfully described the in vitro BuChE activity profile as well as the kinetic parameters. These results support the potential utility of saliva as a biomonitoring matrix for evaluating occupational and environmental exposure to CPF and other OP insecticides.
毒死蜱（CPF）等有机磷（OP）杀虫剂的主要作用机制是其活性氧代代谢产物抑制乙酰胆碱酯酶（AChE），从而产生广泛的神经毒性作用。这些氧代物还会抑制其他胆碱酯酶（ChE），如丁酰胆碱酯酶（BuChE），这代表了一种解毒机制以及OP杀虫剂暴露/反应的潜在生物标志物。唾液生物监测最近已被探索为一种检测化学物质暴露的实用方法，然而，很少有研究探索唾液用于检测OP杀虫剂的情况。为了评估唾液ChE作为OP杀虫剂暴露生物监测指标的用途，采用改良的Ellman测定法结合药效学模型来表征成年雄性Sprague-Dawley大鼠的唾液ChE。在分别存在AChE和BuChE的选择性抑制剂（BW284C51和异-OMPA）的情况下，用不同的ChE底物比较大鼠唾液、脑和血浆中的ChE活性，结果表明大鼠唾液ChE活性主要与BuChE相关（>95%）。对大鼠唾液中BuChE动力学的进一步表征得出，唾液中BuChE活性位点的平均总浓度为1.20±0.13 fmol/ml，平均再活化速率常数（Kr）为0.070±0.008 h-1，抑制速率常数（Ki）约为9 nM-1 h-1。药效学模型成功描述了体外BuChE活性谱以及动力学参数。这些结果支持唾液作为生物监测基质用于评估职业和环境中CPF及其他OP杀虫剂暴露的潜在用途。
