Naturally Occurring Genetic Variants of Human Acetylcholinesterase and Butyrylcholinesterase and Their Potential Impact on the Risk of Toxicity from Cholinesterase Inhibitors.
Naturally Occurring Genetic Variants of Human Acetylcholinesterase and Butyrylcholinesterase and Their Potential Impact on the Risk of Toxicity from Cholinesterase Inhibitors.
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DOI：
10.1021/acs.chemrestox.6b00228
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发表时间：
2016-09-19
影响因子：
4.1
通讯作者：
Blake, Thomas A.
中科院分区：
文献类型：
--
作者：
Lockridge, Oksana;Norgren, Robert B., Jr.;Johnson, Rudolph C.;Blake, Thomas A.
乙酰胆碱酯酶 (AChE) 是神经毒剂和杀虫剂等有机磷毒物 (OP) 的重要生理靶标。血液中的丁酰胆碱酯酶 (BChE) 作为生物清除剂，可保护神经突触中的 AChE 免受 OP 的抑制。质谱法可以通过测量血浆 BChE 活性位点丝氨酸上的加合物来检测 OP 暴露。人类 AChE 和 BChE 的遗传变异确实存在，但仅在 BCHE 基因中发现了功能丧失突变。最常见的 AChE 变体 His353Asn (H322N)，也称为 Yt 血型抗原，具有正常的 AChE 活性。最常见的 BChE 变体 Ala567Thr (A539T) 或纪念 Werner Kalow 的 K 变体的血浆 BChE 活性降低了 33%。最常与肌松剂 Asp98Gly (D70G) 或非典型 BChE 反应延长相关的基因变异，其活性降低，酶浓度降低。在年轻健康男性中进行的早期研究表明，在人体测试神经毒剂是合法的时候，个体对相同低剂量的沙林的反应不同，中毒症状的严重程度从轻微到中度不等。此外，动物研究表明，BChE 可以防护与 AChE 的反应性高于 BChE 的毒物（例如神经毒剂），但不能防护与 BChE 的反应性高于与 AChE 的毒物（例如 OP 农药）。作为推论，我们假设具有 BChE 基因变异的个体可能面临神经毒剂毒性的风险增加，但 OP 农药的毒性风险不会增加。
Acetylcholinesterase (AChE) is the physiologically important target for organophosphorus toxicants (OP) including nerve agents and pesticides. Butyrylcholinesterase (BChE) in blood serves as a bioscavenger that protects AChE in nerve synapses from inhibition by OP. Mass spectrometry methods can detect exposure to OP by measuring adducts on the active site serine of plasma BChE. Genetic variants of human AChE and BChE do exist, but loss of function mutations have been identified only in the BCHE gene. The most common AChE variant, His353Asn (H322N), also known as the Yt blood group antigen, has normal AChE activity. The most common BChE variant, Ala567Thr (A539T) or the K-variant in honor of Werner Kalow, has 33% reduced plasma BChE activity. The genetic variant most frequently associated with prolonged response to muscle relaxants, Asp98Gly (D70G) or atypical BChE, has reduced activity and reduced enzyme concentration. Early studies in young, healthy males, performed at a time when it was legal to test nerve agents in humans, showed that individuals responded differently to the same low dose of sarin with toxic symptoms ranging in severity from minimal to moderate. Additionally, animal studies indicated that BChE protects from toxicants that have a higher reactivity with AChE than with BChE (e.g., nerve agents) but not from toxicants that have a higher reactivity with BChE than with AChE (e.g., OP pesticides). As a corollary, we hypothesize that individuals with genetic variants of BChE may be at increased risk of toxicity from nerve agents but not from OP pesticides.
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影响因子：
4.5
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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