Published: Journal of Analytical Toxicology, ISSN 0146-4760, Volume 32, Number 1, January/February, pp.86-91

A Gas Chromatographic–Mass Spectrometric Approach to Examining Stereoselective Interaction of Human Plasma Proteins with Soman
David T. Yeung[1,2], J. Richard Smith[3], Richard E. Sweeney[4], David E. Lenz[1], and Douglas M. Cerasoli[1],
[1]Physiology and Immunology Branch, Research Division, U.S. Army Medical Research Institute of Chemical Defense, 3100 Ricketts Point Road, Aberdeen Proving Ground, Maryland 21010-5400;
[2]Department of Pharmacology and Experimental Therapeutics, University of Maryland at Baltimore, 655 W. Baltimore Street, Baltimore, Maryland 21201;
[3]Medical Diagnostic and Chemical Branch, Analytical Toxicology Division, U.S. Army Medical Research Institute of Chemical Defense, 3100 Ricketts Point Road, Aberdeen Proving Ground, Maryland 21010-5400; and
[4]RESECO Research Engineering Consultants, P.O. Box 554, Nottingham, Pennsylvania 19362

The organophosphorus (OP) nerve agent soman (GD) contains two chiral centers (a carbon and a phosphorus atom), resulting in four stereoisomers (C+P+, C–P+, C+P–, and C–P–); the P– isomers exhibit a mammalian toxicity that is ~1000-fold greater than that of the P+ isomers. The capacity to assess the binding or hydrolysis of each of the four stereoisomers is an important tool in the development of enzymes with the potential to protect against GD intoxication. Using a gas chromatography–mass spectrometry-based approach, we have examined the capacity of plasma- derived human serum albumin, plasma-purified human butyrylcholinesterase, goat milk-derived recombinant human butyrylcholinesterase, and recombinant human paraoxonase 1 to interact with each of the four stereoisomers of GD in vitro at pH 7.4 and 25°C. Under these experimental conditions, the butyrylcholinesterase samples were found to bind GD with a relative preference for the more toxic stereoisomers (C–P– > C+P– > C–P+ > C+P+), while human serum albumin and paraoxonase 1 interacted with GD with a relative preference for the less toxic isomers (C–P+/C+P+ > C+P–/C–P–). The results indicate that these human proteins exhibit distinct stereoselective interactions with GD. The approach described presents a means to rapidly assess substrate stereospecificity, supporting future efforts to develop more effective OP bioscavenger proteins.

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