title: 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.
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 (k(i)), determined under pseudo-first-order conditions, displayed a biphasic time course of inhibition with k(i) of 1.6 × 10(8) 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 (18)O-water showed that (18)O 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.
authors: Laboratoire de Biophysique Moléculaire, Institut de Biologie Structurale, 41 Rue Jules Horowitz, 38027 Grenoble, France.
authors: Eugénie
authors: E
authors: Carletti
authors: Lawrence M
authors: LM
authors: Schopfer
authors: Jacques-Philippe
authors: JP
authors: Colletier
authors: Marie-Thérèse
authors: MT
authors: Froment
authors: Florian
authors: F
authors: Nachon
authors: Martin
authors: M
authors: Weik
authors: Oksana
authors: O
authors: Lockridge
authors: Patrick
authors: P
authors: Masson
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D016902:Air Pollution, Indoor; D000401:Aircraft; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D018360:Crystallography, X-Ray; D006801:Humans; D007700:Kinetics; D013058:Mass Spectrometry; D008958:Models, Molecular; D020258:Neurotoxicity Syndromes / Q000201:enzymology / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000633:toxicity*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000201:enzymology
chemical_list: D002800:Cholinesterase Inhibitors; D009943:Organophosphorus Compounds; C000516:2-(2-cresyl)-4H-1-3-2-benzodioxaphosphorin-2-oxide; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase