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Download Hi-Res ImageDownload to MS-PowerPointCite This:Chem. Res. Toxicol. 2005, 18, 2, 265-270
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Reactions of Benzene Oxide with Thiols Including Glutathione

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School of Natural SciencesChemistry, Bedson Building, University of Newcastle upon Tyne, Newcastle upon Tyne, NEI 7RU, United Kingdom, Department of Environmental Sciences and Engineering, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7431, National Exposure Research Laboratory, United States Environmental Protection Agency, MD-205-05, Research Triangle Park, North Carolina 27711, and Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, SK10 4TJ, United Kingdom
Cite this: Chem. Res. Toxicol. 2005, 18, 2, 265–270
Publication Date (Web):January 20, 2005
https://doi.org/10.1021/tx049781y
Copyright © 2005 American Chemical Society
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    Abstract

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    S-Phenylmercapturic acid is a minor metabolite of benzene used as a biomarker for human benzene exposures. The reaction of intracellular glutathione with benzene oxide-oxepin, the initial metabolite of benzene, is presumed to give 1-(S-glutathionyl)-cyclohexa-3,5-dien-2-ol, which undergoes dehydration to S-phenylglutathione, the precursor of S-phenylmercapturic acid. To validate the proposed route to S-phenylglutathione, reactions of benzene oxide-oxepin with glutathione and other sulfur nucleophiles have been studied. The reaction of benzene oxide with an excess of aqueous sodium sulfide, followed by acetylation, gave bis-(6-trans-5-acetoxycyclohexa-1,3-dienyl)sulfide, the structure of which was proved by X-ray crystallography. Reactions of benzene oxide-oxepin in a 95:5 (v/v) mixture of phosphate buffer in D2O with (CD3)2SO were monitored by 1H NMR spectroscopy. In the absence of glutathione, the half-life of benzene oxide-oxepin was ca. 34 min at 25 °C and pD 7.0. The half-life was not affected in the range of 2−15 mM glutathione in the presence and absence of a commercial sample of human glutathione S-transferase (at pH 7.0, 8.0, 8.5, or 10.0). The adduct 1-(S-glutathionyl)-cyclohexa-3,5-diene-2-ol was identified in these reaction mixtures, especially at higher pH, by mass spectrometry and by its acid-catalyzed decomposition to S-phenylglutathione. Incubation of benzene oxide with N-acetyl-l-cysteine at 37 °C and pH 10.0 and subsequent mass spectrometric analysis of the mixture showed formation of pre-S-phenylmercapturic acid and the dehydration product, S-phenylmercapturic acid. The data validate the premise that benzene oxide-oxepin can be captured by glutathione to give (1R,2R)- and/or (1S,2S)-1-(S-glutathionyl)-cyclohexa-3,5-dien-2-ol, which dehydrate to S-phenylglutathione. The capture is a relatively inefficient process at pH 7 that is accelerated at higher pH. These studies account for the observation that the metabolism of benzene is dominated by the formation of phenol. The pathway leading to S-phenylmercapturic acid is necessarily minor on account of the low efficiency of benzene oxide capture by glutathione at pH 7 vs spontaneous rearrangement to phenol.

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    *

     To whom correspondence should be addressed. (A.P.H.) Tel:  1 + 919 + 9667319. Fax:  1 + 919 + 9664711. E-mail:  [email protected]. (B.T.G.) Tel:  44 + 191 + 2226647. Fax:  44 + 191 + 2226929. E-mail:  [email protected].

    †

     University of Newcastle upon Tyne.

    ‡

     University of North Carolina at Chapel Hill.

    §

     United States Environmental Protection Agency.

    ‖

     Syngenta Central Toxicology Laboratory.

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