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GLUTATHIONE S-TRANSFERASE-MEDIATED METABOLISM OF BROMODICHLOROMETHANE
Citation:
Ross, M. K. AND R A. Pegram. GLUTATHIONE S-TRANSFERASE-MEDIATED METABOLISM OF BROMODICHLOROMETHANE. Presented at SOT, San Francisco, CA, March 25-29, 2001.
Description:
GLUTATHIONE s-TRANSFERASE-MEDIATED METABOLISM OF BROMODICHLOROMETHANE. M K Ross1 and R A Pegram2. 1Curriculum in Toxicology, University of North Carolina at Chapel Hill; 2Experimental Toxicology Division, NHEERL/ORD, United States Environmental Protection Agency, Research Triangle Park, NC, USA.
Sponsor: H. Barton
The glutathione S-transferase (GST)-mediated metabolism and DNA binding potential of the disinfection-by-product bromodichloromethane (BDCM) is currently under investigation. BDCM was previously shown to be a mutagen in a Salmonella typhimurium strain transformed with rat GST theta 1-1. In vitro incubation of [14C]-BDCM in the presence of mouse hepatic cytosol and supplemented glutathione (GSH) resulted in the production of multiple polar products (~ 3-7% of the dose), as determined by a reversed-phase HPLC assay with in-line radioactive flow detection. The identities of these polar metabolites are currently unknown; however, a GSH-dependent product detected (~ 1-2% of the dose) after incubation of [14C]-BDCM with GSH in the absence of cytosol was tentatively assigned the structure S-[14C]-formyl-GSH. This assignment is based upon hydrolysis experiments demonstrating that under alkaline conditions (pH 13) the putative S-[14C]-formyl-GSH was hydrolyzed to a single polar product that co-eluted with authentic formic acid by HPLC. S-[14C]-formyl-GSH was not observed when cytosol was present in the incubation mixture. Additionally, incubation of purified S-[14C]-formyl-GSH with dialyzed mouse hepatic cytosol led to the quantitative formation of a [14C]-polar product that was subsequently volatilized upon acidification, suggesting formation of 14CO2. It is proposed that S-[14C]-formyl-GSH is a transient intermediate derived from [14C]-BDCM that is subsequently hydrolyzed to [14C]-formate by an S-formyl-GSH hydrolase activity found in mouse hepatic cytosol; formate dehydrogenase in cytosol may then further oxidize [14C]-formate to yield 14CO2. Reactive intermediates en route to S-formyl-GSH are postulated to form with the capacity to induce pre-mutagenic DNA lesions during GST-mediated biotransformation of BDCM. (This abstract does not reflect EPA policy.)