Molecular Structure and Conformation of 4<i>H</i>-1,3,2-Benzodioxaphosphorins, Including the Insecticide Salithion

Etō, Morifusa; Fukuhara, Nobuhiro; Kuwanoand, Eiichi; Koyama, H.

doi:10.1080/00021369.1981.10864614

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“…Saligenin-derived, six-membered cyclic phosphates (oxon) are even more sensitive to hydrolysis . Instability of these compounds is reported to be due to a strain in the distorted benzodioxaphosphorin ring. , …”

Section: Resultsmentioning

confidence: 99%

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

Schopfer

Colletier

et al. 2011

Chem. Res. Toxicol.

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The aerotoxic syndrome is assumed to be caused by exposure to tricresyl phosphate (TCP), an anti-wear additive in jet engine lubricants and hydraulic fluids. CBDP (2-(ortho-cresyl)-4H-1,2,3-benzodioxaphosphoran-2-one) is the toxic metabolite of tri-ortho-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 1.6×108 M−1min−1 and 2.7×107 M−1min−1 for E and E′ forms of BChE. The inhibition constants for AChE were one to two orders of magnitude slower than for BChE. CBDP-phosphorylated cholinesterases are non-reactivatable 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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Section: Resultsmentioning

confidence: 99%