Reaction of Cresyl Saligenin Phosphate, the Organophosphorus Agent Implicated in Aerotoxic Syndrome, with Human Cholinesterases: Mechanistic Studies Employing Kinetics, Mass Spectrometry, and X-ray St

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• 作者：Euge虂nie Carletti ; Lawrence M. Schopfer ; Jacques-Philippe Colletier ; Marie-The虂re虁se Froment ; Florian Nachon ; Martin Weik ; Oksana Lockridge ; Patrick Masson
• 刊名：Chemical Research in Toxicology
• 出版年：2011
• 出版时间：June 20, 2011
• 年：2011
• 卷：24
• 期：6
• 页码：797-808
• 全文大小：986K
• 年卷期：v.24,no.6(June 20, 2011)
• ISSN：1520-5010

文摘

Aerotoxic syndrome is assumed to be caused by exposure to tricresyl phosphate (TCP), an antiwear additive in jet engine lubricants and hydraulic fluid. CBDP (2-(ortho-cresyl)-4H-1,2,3-benzodioxaphosphoran-2-one) is the toxic metabolite of triortho-cresylphosphate, a component of TCP. Human butyrylcholinesterase (BChE; EC 3.1.1.8) and human acetylcholinesterase (AChE; EC 3.1.1.7) are irreversibly inhibited by CBDP. The bimolecular rate constants of inhibition (k_i), determined under pseudo-first-order conditions, displayed a biphasic time course of inhibition with k_i of 1.6 脳 10⁸ M^鈭? min^鈭? and 2.7 脳 10⁷ M^鈭? min^鈭? for E and E鈥?forms of BChE. The inhibition constants for AChE were 1 to 2 orders of magnitude slower than those for BChE. CBDP-phosphorylated cholinesterases are nonreactivatable due to ultra fast aging. Mass spectrometry analysis showed an initial BChE adduct with an added mass of 170 Da from cresylphosphate, followed by dealkylation to a structure with an added mass of 80 Da. Mass spectrometry in ¹⁸O-water showed that ¹⁸O was incorporated only during the final aging step to form phospho-serine as the final aged BChE adduct. The crystal structure of CBDP-inhibited BChE confirmed that the phosphate adduct is the ultimate aging product. CBDP is the first organophosphorus agent that leads to a fully dealkylated phospho-serine BChE adduct.