Pesticide Chemical Research in Toxicology: Lessons from Nature
Pesticide Chemical Research in Toxicology: Lessons from Nature
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DOI：
10.1021/acs.chemrestox.6b00303
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发表时间：
2017-01-01
影响因子：
4.1
通讯作者：
Durkin, Kathleen A.
中科院分区：
文献类型：
--
作者：
Casida, John E.;Durkin, Kathleen A.
农药研究人员是大自然的学生，每一种新的化合物和机制都在不断扩大的生命百科全书中翻开了一页。农药既是了解生命过程的探针，也是害虫管理的工具，以促进粮食生产和增进健康。与某些家用和工业化学品不同，农药被认为对健康和环境有害，除非有相反的证据。目前约有1000种农药通过100多种不同的机制发挥作用，有助于了解许多过程和耦合事件。农药化学研究是关于新天然产物、新靶标或作用模式、抗性机制、异生物质代谢、选择性毒性、安全性评价以及安全有效的害虫管理建议的毒理学信息的主要来源。靶结合位点模型有助于确定取代基变化的影响，并预测修饰以增强效力和安全性并规避耐药性。农药化学研究在毒理学中的贡献在这里用两种较新或最重要的杀虫剂，除草剂和杀菌剂来说明。杀虫剂是吡虫啉和氯虫苯甲酰胺，分别作用于烟碱乙酰胆碱受体和兰尼碱受体Ca 2+通道。除草剂是抑制芳香族氨基酸生物合成的草甘膦和防止质体醌和类胡萝卜素形成的甲基磺草酮。杀真菌剂是抑制细胞色素bc（1）复合物的Q（0）位点的嘧菌酯和抑制麦角甾醇生物合成中的14 α-脱甲基酶的丙硫菌唑。每种杀虫剂涉及的两个目标地点占全球所有杀虫剂，除草剂和杀真菌剂销售额的27-40%。在每一种情况下，涉及结合位点或解毒酶的单个氨基酸变化的抗性选择绕过了农药化学家的结构优化，并保证了害虫的生存和设计化学家的持续工作。这些来自大自然的教训是害虫管理和维护人类和环境健康的持续组成部分。
Pesticide researchers are students of nature, and each new compound and mechanism turns a page in the ever-expanding encyclopedia of life. Pesticides are both probes to learn about life processes and tools for pest management to facilitate food production and enhance health. In contrast to some household and industrial chemicals, pesticides are assumed to be hazardous to health and the environment until proven otherwise. About a thousand current pesticides working by more than 100 different mechanisms have helped understand many processes and coupled events. Pesticide chemical research is a major source of toxicology information on new natural products, novel targets or modes of action, resistance mechanisms, xenobiotic metabolism, selective toxicity, safety evaluations, and recommendations for safe and effective pest management. Target binding site models help define the effect of substituent changes and predict modifications for enhanced potency and safety and circumvention of resistance. The contribution of pesticide chemical research in toxicology is illustrated here with two each of the newer or most important insecticides, herbicides, and fungicides. The insecticides are imidacloprid and chlorantraniliprole acting on the nicotinic acetylcholine receptor and the ryanodine receptor Ca2+ channel, respectively. The herbicides are glyphosate that inhibits aromatic amino acid biosynthesis and mesotrione that prevents plastoquinone and carotenoid formation. The fungicides are azoxystrobin inhibiting the Q(0) site of the cytochrome bc(1) complex and prothioconazole inhibiting the 14 alpha-demethylase in ergosterol biosynthesis. The two target sites involved for each type of pesticide account for 27-40% of worldwide sales for all insecticides, herbicides, and fungicides. In each case, selection for resistance involving a single amino acid change in the binding site or detoxifying enzyme circumvents the pesticide chemists's structure optimization and guarantees survival of the pest and a continuing job for the design chemist. These lessons from nature are a continuing part of pest management and maintaining human and environmental health.