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Metabolism of 1,1-and 1,3-Dichloropropene: A Mechanism of Bioactivation By Glutathione

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Abstract: Glutathione transferases (GST) catalyze the reaction of glutathione (GSH) with haloalkenes via a nucleophilic vinylic substitution mechanism (SNV reaction). The source water contaminants 1,1-dichloropropene and 1,3-dichloropropene, which are under scrutiny by the U.S.EPA, were examined for their ability to produce S-conjugates of GSH and to produce genotoxic species as a result. Following in vitro reactions of 1,1- and 1,3-dichloropropenes with mouse liver cytosol and supplemented GSH, the products were examined by LC-MS and LC-MS/MS analyses. The presence of m/z 382/384 ions following reaction with both 1,1-dichloropropene and 1,3-dichloropropene confirmed the production of stable mono S-conjugates of GSH containing a single Cl atom. LC-MS/MS analysis (SRM m/z 382 - m/z 253) provided a sensitive means of detecting the GSH conjugate of 1,1-dichloropropene since it was much less reactive than 1,3-dichloropropene toward GSH. The significance of GSH conjugation of 1,1-dichloropropene is that Salmonella typhimurium transformed with GSTT5 (rat) or GSTT1 (human) cDNA produced mutations following exposure to 1,1-dichloropropene. The mutations were dependent on the presence of the GST isozyme. In contrast, 1,3-dichloropropene was not mutagenic in the same strains of bacteria. An addition-elimination mechanism is proposed that can account for the production of the stable S-conjugate(s) of 1,1-dichloropropene (m/z 382/384) in addition to the formation of a transient episulfonium ion that may be the genotoxic species responsible for the mutations produced in the bacterial strains.

This work has been funded by the United States Environmental Protection Agency. It has been subjected to Agency review and approved for publication.

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Citation:Ross, M. K., R. Tornero-Velez, C. Granville, A. Gold, M. V. Evans, and D. M. Demarini. Metabolism of 1,1-and 1,3-Dichloropropene: A Mechanism of Bioactivation By Glutathione. Presented at International Society for the Study of Xenobiotics, Vancouver, Canada, August 29-September 2, 2004.
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Contact: Liz Hope - (919) 541-2785 or hope.elizabeth@epa.gov
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Division: Human Exposure & Atmospheric Sciences Division
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Branch: Exposure & Dose Research Branch
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Product Type: Abstrct/Oral
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Presented: 08/31/2004
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Related Entries:
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Bullet Item Models and Modeling Methods for Assessing Human Exposure and Dose to Toxic Chemicals and Pollutants
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Last Updated on Monday, October 22, 2007
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