Thiodiglycol, the hydrolysis product of sulfur mustard: Analysis of in vitro biotransformation by mammalian alcohol dehydrogenases using nuclear magnetic resonance

Brimfield, A A; Novak, Mark J; Hodgson, Ernest

doi:10.1016/j.taap.2005.11.009

Title: Thiodiglycol, the hydrolysis product of sulfur mustard: Analysis of in vitro biotransformation by mammalian alcohol dehydrogenases using nuclear magnetic resonance

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Abstract

Thiodiglycol (2,2'-bis-hydroxyethylsulfide, TDG), the hydrolysis product of the chemical warfare agent sulfur mustard, has been implicated in the toxicity of sulfur mustard through the inhibition of protein phosphatases in mouse liver cytosol. The absence of any inhibitory activity when TDG was present in assays of pure enzymes, however, led us to investigate the possibility for metabolic activation of TDG to inhibitory compound(s) by cytosolic enzymes. We have successfully shown that mammalian alcohol dehydrogenases (ADH) rapidly oxidize TDG in vitro, but the classic spectrophotometric techniques for following this reaction provided no information on the identity of TDG intermediates and products. The use of proton NMR to monitor the oxidative reaction with structural confirmation by independent synthesis allowed us to establish the ultimate product, 2-hydroxyethylthioacetic acid, and to identify an intermediate equilibrium mixture consisting of 2-hydroxyethylthioacetaldehyde, 2-hydroxyethylthioacetaldehyde hydrate and the cyclic 1,4-oxathian-2-ol. The intermediate nature of this mixture was determined spectrophotometrically when it was shown to drive the production of NADH when added to ADH and NAD.

Authors:

Brimfield, A A ^[1]; Novak, Mark J ^[2]; Hodgson, Ernest ^[3]

Pharmacology Division, U.S. Army Medical Research Institute of Chemical Defense, 3100 Ricketts Point Rd. Aberdeen Proving Ground/Edgewood Area, MD 21010-5400 (United States)
Department of Chemistry, Florida Institute of Technology, Melbourne, FL 32901 (United States)
Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC 27695 (United States)

Publication Date:: Thu Jun 15 00:00:00 EDT 2006

OSTI Identifier:: 20850343

Resource Type:: Journal Article

Journal Name:: Toxicology and Applied Pharmacology

Additional Journal Information:: Journal Volume: 213; Journal Issue: 3; Other Information: DOI: 10.1016/j.taap.2005.11.009; PII: S0041-008X(05)00653-8; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X

Country of Publication:: United States

Language:: English

Subject:: 60 APPLIED LIFE SCIENCES; ALCOHOL DEHYDROGENASE; ALCOHOLS; BRASSICA; CHEMICAL WARFARE AGENTS; HYDRATES; HYDROLYSIS; IN VITRO; LIVER; METABOLIC ACTIVATION; MICE; NAD; NUCLEAR MAGNETIC RESONANCE; PHOSPHATASES; SULFUR; SYNTHESIS; TOXICITY

Citation Formats


                    Brimfield, A A, Novak, Mark J, and Hodgson, Ernest. Thiodiglycol, the hydrolysis product of sulfur mustard: Analysis of in vitro biotransformation by mammalian alcohol dehydrogenases using nuclear magnetic resonance.  United States: N. p., 2006. 
        Web.  doi:10.1016/j.taap.2005.11.009.

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                    Brimfield, A A, Novak, Mark J, & Hodgson, Ernest. Thiodiglycol, the hydrolysis product of sulfur mustard: Analysis of in vitro biotransformation by mammalian alcohol dehydrogenases using nuclear magnetic resonance.  United States.  https://doi.org/10.1016/j.taap.2005.11.009

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                    Brimfield, A A, Novak, Mark J, and Hodgson, Ernest. 2006.  
        "Thiodiglycol, the hydrolysis product of sulfur mustard: Analysis of in vitro biotransformation by mammalian alcohol dehydrogenases using nuclear magnetic resonance".  United States.  https://doi.org/10.1016/j.taap.2005.11.009.

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@article{osti_20850343,

  title        = {Thiodiglycol, the hydrolysis product of sulfur mustard: Analysis of in vitro biotransformation by mammalian alcohol dehydrogenases using nuclear magnetic resonance},

  author       = {Brimfield, A A and Novak, Mark J and Hodgson, Ernest},

  abstractNote = {Thiodiglycol (2,2'-bis-hydroxyethylsulfide, TDG), the hydrolysis product of the chemical warfare agent sulfur mustard, has been implicated in the toxicity of sulfur mustard through the inhibition of protein phosphatases in mouse liver cytosol. The absence of any inhibitory activity when TDG was present in assays of pure enzymes, however, led us to investigate the possibility for metabolic activation of TDG to inhibitory compound(s) by cytosolic enzymes. We have successfully shown that mammalian alcohol dehydrogenases (ADH) rapidly oxidize TDG in vitro, but the classic spectrophotometric techniques for following this reaction provided no information on the identity of TDG intermediates and products. The use of proton NMR to monitor the oxidative reaction with structural confirmation by independent synthesis allowed us to establish the ultimate product, 2-hydroxyethylthioacetic acid, and to identify an intermediate equilibrium mixture consisting of 2-hydroxyethylthioacetaldehyde, 2-hydroxyethylthioacetaldehyde hydrate and the cyclic 1,4-oxathian-2-ol. The intermediate nature of this mixture was determined spectrophotometrically when it was shown to drive the production of NADH when added to ADH and NAD.},

  doi          = {10.1016/j.taap.2005.11.009},

  url          = {https://www.osti.gov/biblio/20850343},
  journal      = {Toxicology and Applied Pharmacology},

  issn         = {0041-008X},

  number       = 3,

  volume       = 213,

  place        = {United States},

  year         = {Thu Jun 15 00:00:00 EDT 2006},

  month        = {Thu Jun 15 00:00:00 EDT 2006}

}

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