Mahajna M, Casida J E
Department of Environmental Science, Policy and Management, University of California, Berkeley 94720-3112, USA.
Chem Res Toxicol. 1998 Jan;11(1):26-34. doi: 10.1021/tx9701135.
The systemic insecticide methamidophos, MeO(MeS)P(O)NH2, is a very weak inhibitor of acetylcholinesterase (AChE) in vitro relative to in vivo suggesting bioactivation. This hypothesis is supported by finding that brain AChE inhibition and poisoning signs from methamidophos are greatly delayed in mice and houseflies pretreated with oxidase inhibitors in an order for effectiveness of methimazole > N-benzylimidazole >> piperonyl butoxide. In contrast, the order for delaying parathion-induced AChE inhibition and toxicity is N-benzylimidazole >> piperonyl butoxide or methimazole, suggesting that different oxidases are involved in methamidophos and parathion activation. N-Hydroxylation is examined here as an alternative to the controversial S-oxidation proposed earlier for methamidophos activation. N-Hydroxymethamidophos [MeO(MeS)P(O)NHOH], synthesized by coupling MeO(MeS)P(O)Cl and Me3SiNHOSiMe3 followed by desilylation, is unstable at pH 7.4 (t1/2 = 10 min at 37 degrees C) with decomposition by two distinct and novel mechanisms. The first mechanism (A) is N-->O rearrangement to MeO(MeS)P(O)ONH2 and then hydrolysis to MeO(MeS)P(O)OH, a sequence also established in the analogous series of (MeO)2P(O)NHOH-->(MeO)2P(O)ONH2-->(MeO)2P(O)OH. The second mechanism (B) is proposed to involve tautomerism to the phosphimino form [MeO(MeS)P(OH)=NOH] that eliminates MeSH forming a metaphosphate analogue [MeOP(O)=NOH] trapped by water to give MeO(HO)P(O)NHOH that undergoes the N-->O rearrangement as above and hydrolysis to MeOP(O)(OH)2. As a metaphosphate analogue, the metaphosphorimidate generated from MeO(MeS)P(O)NHOH in aqueous ethanol yields MeOP(O)(OH)2 and MeO(EtO)P(O)OH in the same ratio as the solvents on a molar basis. Reactions of the N- and O-methyl derivatives of MeO(MeS)P(O)NHOH and (MeO)2P(O)NHOH are consistent with proposed mechanisms A and B. N-Hydroxymethamidophos is less potent than methamidophos as an AChE inhibitor and toxicant possibly associated with its rapid hydrolysis. Bioactivation of methamidophos via a metaphosphate analogue would directly yield a phosphorylated and aged AChE resistant to reactivating agents, an intriguing hypothesis worthy of further consideration.
内吸性杀虫剂甲胺磷（MeO(MeS)P(O)NH₂）在体外对乙酰胆碱酯酶（AChE）的抑制作用相对于体内而言非常弱，这表明存在生物活化作用。这一假设得到了以下发现的支持：在用氧化酶抑制剂预处理的小鼠和家蝇中，甲胺磷对脑AChE的抑制作用和中毒症状会大大延迟，其抑制效果顺序为甲巯咪唑＞N - 苄基咪唑＞＞胡椒基丁醚。相比之下，延迟对硫磷诱导的AChE抑制作用和毒性的顺序为N - 苄基咪唑＞＞胡椒基丁醚或甲巯咪唑，这表明甲胺磷和对硫磷的活化涉及不同的氧化酶。本文研究了N - 羟基化作为一种替代方案，以替代先前提出的有争议的甲胺磷S - 氧化活化机制。通过将MeO(MeS)P(O)Cl与Me₃SiNHOSiMe₃偶联，随后进行去硅烷基化反应合成的N - 羟基甲胺磷[MeO(MeS)P(O)NHOH]在pH 7.4时不稳定（37℃下t₁/₂ = 10分钟），通过两种不同的新机制分解。第一种机制（A）是N→O重排为MeO(MeS)P(O)ONH₂，然后水解为MeO(MeS)P(O)OH，这一序列在(MeO)₂P(O)NHOH→(MeO)₂P(O)ONH₂→(MeO)₂P(O)OH的类似系列中也已确定。第二种机制（B）被认为涉及互变异构为磷亚氨基形式[MeO(MeS)P(OH)=NOH]，消除MeSH形成一个被水捕获的偏磷酸盐类似物[MeOP(O)=NOH]，生成MeO(HO)P(O)NHOH，其经历上述N→O重排并水解为MeOP(O)(OH)₂。作为偏磷酸盐类似物，在乙醇水溶液中由MeO(MeS)P(O)NHOH生成的偏磷亚氨酸酯以与溶剂摩尔比相同的比例生成MeOP(O)(OH)₂和MeO(EtO)P(O)OH。MeO(MeS)P(O)NHOH和(MeO)₂P(O)NHOH的N - 和O - 甲基衍生物的反应与所提出的机制A和B一致。N - 羟基甲胺磷作为AChE抑制剂和毒物的效力低于甲胺磷，这可能与其快速水解有关。通过偏磷酸盐类似物对甲胺磷进行生物活化将直接产生一种对重活化剂具有抗性的磷酸化且老化的AChE，这是一个值得进一步考虑的有趣假设。
