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

Research output: Contribution to journalArticle

39 Citations (Scopus)

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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Cholinesterases
Mass spectrometry
Mass Spectrometry
Phosphates
X-Rays
Tritolyl Phosphates
X rays
Kinetics
Aging of materials
Serine
Dealkylation
Butyrylcholinesterase
Lubricants
Hydraulic fluids
Jet engines
Poisons
Acetylcholinesterase
Metabolites
Rate constants
Crystal structure

ASJC Scopus subject areas

  • Toxicology

Cite this

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

In: Chemical Research in Toxicology, Vol. 24, No. 6, 20.06.2011, p. 797-808.

Research output: Contribution to journalArticle

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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.",
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AU - Schopfer, Lawrence M

AU - Colletier, Jacques Philippe

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AU - Masson, Patrick

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