Davies H G, Richter R J, Keifer M, Broomfield C A, Sowalla J, Furlong C E
Department of Genetics, University of Washington, Seattle 98195-7360, USA.
Nat Genet. 1996 Nov;14(3):334-6. doi: 10.1038/ng1196-334.
Many organophosphorus compounds (OPs) are potent cholinesterase inhibitors, accounting for their use as insecticides and, unfortunately, also as nerve agents. Each year there are approximately 3 million pesticide poisonings world-wide resulting in 220,00 deaths. In 1990, there were 1.36 million kg of chlorpyrifos, 4.67 million kg of diazinon and 1.23 million kg of ethyl parathion manufactured in the USA (data supplied by the USEPA). In addition to exposure risks during pesticide manufacturing, distribution and use, there are risks associated with the major international effort aimed at destroying the arsenals of nerve agents, including soman and sarin. The United States has pledged to destroy approximately 25,000 tons of chemical agents by the end of the decade. The high density lipoprotein (HDL)-associated enzyme paraoxonase (PON1) contributes significantly to the detoxication of several OPs (Fig. 1). The insecticides parathion, chlorpyrifos and diazinon are bioactivated to potent cholinesterase inhibitors by cytochrome P-450 systems. The resulting toxic oxon forms can be hydrolysed by PON1, which also hydrolyses the nerve agents soman and sarin (Fig. 1). PON1 is polymorphic in human populations and different individuals also express widely different levels of this enzyme. The Arg192 (R192) PON1 isoform hydrolyses paraoxon rapidly, while the Gln192 (Q191) isoform hydrolyses paraoxon slowly. Both isoforms hydrolyse chlorpyrifos-oxon and phenylacetate at approximately the same rate. The role of PON1 in OP detoxication is physiologically significant. Injected PON1 protects against OP poisoning in rodent model systems and interspecies differences in PON1 activity correlate well with observed median lethal dose (LD50) values. We report here a simple enzyme analysis that provides a clear resolution of PON1 genotypes and phenotypes allowing for a reasonable assessment of an individual's probable susceptibility or resistance to a given OP, extending earlier studies on this system. We also show that the effect of the PON1 polymorphism is reversed for the hydrolysis of diazoxon, soman and especially sarin, thus changing the view of which PON1 isoform is considered to be protective.
许多有机磷化合物（OPs）是强效胆碱酯酶抑制剂，这也是它们被用作杀虫剂的原因，不幸的是，它们也被用作神经毒剂。全球每年约有300万人农药中毒，导致22万人死亡。1990年，美国生产了136万千克毒死蜱、467万千克二嗪农和123万千克对硫磷（数据由美国环境保护局提供）。除了在农药生产、分销和使用过程中的接触风险外，还有与旨在销毁包括梭曼和沙林在内的神经毒剂库的重大国际行动相关的风险。美国已承诺在本十年末销毁约2.5万吨化学毒剂。高密度脂蛋白（HDL）相关酶对氧磷酶（PON1）对几种OPs的解毒作用有显著贡献（图1）。杀虫剂对硫磷、毒死蜱和二嗪农被细胞色素P - 450系统生物活化成强效胆碱酯酶抑制剂。产生的有毒氧磷形式可被PON1水解，PON1也能水解神经毒剂梭曼和沙林（图1）。PON1在人类群体中具有多态性，不同个体表达的这种酶水平也差异很大。精氨酸192（R192）PON1同工型能快速水解对氧磷，而谷氨酰胺192（Q191）同工型水解对氧磷较慢。两种同工型水解毒死蜱氧磷和苯乙酸的速度大致相同。PON1在OP解毒中的作用具有生理意义。在啮齿动物模型系统中，注射PON1可预防OP中毒，并且PON1活性的种间差异与观察到的半数致死剂量（LD50）值密切相关。我们在此报告一种简单的酶分析方法，该方法能清晰区分PON1基因型和表型，从而合理评估个体对给定OP可能的易感性或抗性，扩展了此前对该系统的研究。我们还表明，对于二唑磷、梭曼尤其是沙林的水解，PON1多态性的影响是相反的，从而改变了哪种PON1同工型被认为具有保护作用的观点。
