Casida John E, Quistad Gary B
Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, CA 94720-3112, USA.
Chem Biol Interact. 2005 Dec 15;157-158:277-83. doi: 10.1016/j.cbi.2005.10.036. Epub 2005 Oct 21.
Acetylcholinesterase (AChE) is one of several hundred serine hydrolases in people potentially exposed to about 80 organophosphorus (OP) compounds important as insecticides or chemical warfare agents. The toxicology of OPs was interpreted until recently almost solely on the basis of AChE inhibition. It is assumed that each serine hydrolase has a specific function and proposed that every OP compound has a unique inhibitory profile. This review considers the progress in sifting the expanding list of potential serine hydrolase toxicological targets. About 50 serine hydrolase targets have been recognized but only a few studied thoroughly. The toxicological relevance of known secondary OP targets is established mainly from observations with humans (butyrylcholinesterase and neuropathy target esterase-lysophospholipase) and studies with mice (cannabinoid CB1 receptor, carboxylesterase, lysophospholipase and platelet activating factor acetylhydrolase) and hen eggs (arylformamidase or kynurenine formamidase). Pesticides most commonly shown to inhibit these targets in experimental vertebrates are chlorpyrifos and tribufos. Generally the levels of environmental and occupational OP pesticide exposure are well below those causing in vivo inhibition of secondary serine hydrolase targets. Although exposure to OP insecticides is decreasing from stricter regulations and the development of resistant pest strains, it will continue to some degree for decades in the future. Only two OPs are used as pharmaceuticals, i.e. echothiophate as an ophthalmic for treatment of glaucoma and metrifonate as an anthelmintic for Schistosoma (and formerly as a candidate drug for improved cognitive function in Alzheimer's disease). In safety evaluations, knowledge on known OP targets must be balanced against major gaps in current understanding since more than 75% of the serine hydrolases are essentially unknown as to OP targeting and relevance, i.e. it is not clear if they play a role in OP toxicology.
乙酰胆碱酯酶（AChE）是数百种丝氨酸水解酶之一，存在于可能接触约80种有机磷（OP）化合物的人群中，这些化合物作为杀虫剂或化学战剂具有重要意义。直到最近，OP的毒理学几乎完全是基于对AChE的抑制作用来解释的。据推测，每种丝氨酸水解酶都有特定的功能，并提出每种OP化合物都有独特的抑制谱。本综述考虑了在筛选不断扩大的潜在丝氨酸水解酶毒理学靶点列表方面取得的进展。已经识别出约50个丝氨酸水解酶靶点，但只有少数得到了深入研究。已知的OP次要靶点的毒理学相关性主要是通过对人类的观察（丁酰胆碱酯酶和神经病变靶标酯酶-溶血磷脂酶）、对小鼠的研究（大麻素CB1受体、羧酸酯酶、溶血磷脂酶和血小板活化因子乙酰水解酶）以及对鸡蛋的研究（芳基甲酰胺酶或犬尿氨酸甲酰胺酶）确定的。在实验脊椎动物中最常显示能抑制这些靶点的农药是毒死蜱和三丁锡。一般来说，环境和职业性OP农药暴露水平远低于导致体内次要丝氨酸水解酶靶点受到抑制的水平。尽管由于更严格的法规和抗药性害虫品系的发展，OP杀虫剂暴露量正在下降，但在未来几十年内仍将在一定程度上持续存在。只有两种OP被用作药物，即碘磷灵作为治疗青光眼的眼科用药，以及敌百虫作为治疗血吸虫的驱虫药（以前曾作为改善阿尔茨海默病认知功能的候选药物）。在安全性评估中，关于已知OP靶点的知识必须与当前理解中的重大差距相权衡，因为超过75%的丝氨酸水解酶在OP靶向作用和相关性方面基本上是未知的，即尚不清楚它们是否在OP毒理学中发挥作用。
