Reaction of cresyl saligenin phosphate, the organophosphorus agent implicated in aerotoxic syndrome, with human cholinesterases: Mechanistic studies employing kinetics, mass spectrometry, and X-ray structure analysis

Eugénie Carletti, Lawrence M. Schopfer, Jacques Philippe Colletier, Marie Thérèse Froment, Florian Nachon, Martin Weik, Oksana Lockridge, Patrick Masson

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Abstract

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 (ki), determined under pseudo-first-order conditions, displayed a biphasic time course of inhibition with ki of 1.6 ×108 M-1 min-1 and 2.7 ×10 7 M-1 min-1 for E and E′ 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.

Original languageEnglish (US)
Pages (from-to)797-808
Number of pages12
JournalChemical Research in Toxicology
Volume24
Issue number6
DOIs
StatePublished - Jun 20 2011

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ASJC Scopus subject areas

  • Toxicology

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