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Quantitation of ortho-cresyl phosphate adducts to butyrylcholinesterase in human serum by immunomagnetic-UHPLC-MS/MS

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Author: Johnson, D. · Carter, M.D. · Crow, B.S. · Isenberg, S.L. · Graham, L.A. · Erol, H.A. · Watson, C.M. · Pantazides, B.G. · Schans, M.J. van der · Langenberg, J.P. · Noort, D. · Blake, T.A. · Thomas, J.D. · Johnson, R.C.
Publisher: John Wiley and Sons Ltd
Source:Journal of Mass Spectrometry, 4, 50, 683-692
Identifier: 527060
doi: doi:10.1002/jms.3576
Keywords: Butyrylcholinesterase · Dresyl saligenin phosphate · Jamaica ginger paralysis · Organophosphate-induced delayed neuropathy · Tri-ortho-cresyl-phosphate · Body fluids · Cabins (aircraft) · Calibration · Enzymes · Lubricants · Tribology · Butyrylcholinesterase · Esterase enzymes · Flame-retardant additives · Human exposures · Industrial lubricants · Jamaica · Neurotoxic effects · Organophosphate-induced delayed neuropathy · Cockpits (aircraft) · Cholinesterase · Tri ortho cresyl phosphate · Accuracy · Cholinesterase blood level · Controlled study · In vitro study · Limit of detection · Tandem mass spectrometry · Ultra performance liquid chromatography · Zingiber officinale · Observation, Weapon & Protection Systems · CBRN - CBRN Protection · TS - Technical Sciences


Tri-ortho-cresyl phosphate (ToCP) is an anti-wear, flame retardant additive used in industrial lubricants, hydraulic fluids and gasoline. The neurotoxic effects of ToCP arise from the liver-activated metabolite 2-(o-cresyl)-4H-1,3,2-benzodioxaphosphoran-2-one (cresyl saligenin phosphate or CBDP), which inhibits esterase enzymes including butyrylcholinesterase (BChE). Following BChE adduction, CBDP undergoes hydrolysis to form the aged adduct ortho-cresyl phosphoserine (oCP-BChE), thus providing a biomarker of CBDP exposure. Previous studies have identified ToCP in aircraft cabin and cockpit air, but assessing human exposure has been hampered by the lack of a laboratory assay to confirm exposure. This work presents the development of an immunomagnetic-UHPLC-MS/MS method for the quantitation of unadducted BChE and the long-term CBDP biomarker, oCP-BChE, in human serum. The method has a reportable range from 2.0ng/ml to 150ng/ml, which is consistent with the sensitivity of methods used to detect organophosphorus nerve agent protein adducts. The assay demonstrated high intraday and interday accuracy (≥85%) and precision (RSD≤15%) across the calibration range. The method was developed for future analyses of potential human exposure to CBDP. Analysis of human serum inhibited in vitro with CBDP demonstrated that the oCP-BChE adduct was stable for at least 72h at 4, 22 and 37 C. Compared to a previously reported assay, this method requires 75% less sample volume, reduces analysis time by a factor of 20 and demonstrates a threefold improvement in sensitivity. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. © Published 2015. This article is a U.S. Government work and is in the public domain in the USA.