title: Metabolism and mutagenicity of source water contaminants 1,3-dichloropropane and 2,2-dichloropropane.
abstract: Cytochrome P450-dependent oxidation and glutathione (GSH)-dependent conjugation are the primary routes of metabolism of haloalkanes. Using rat liver microsomes and cytosol, we investigated the metabolism of two halopropanes found on the U.S. Environmental Protection Agency Contaminant Candidate List, 1,3-dichloropropane (1,3-DCP) and 2,2-dichloropropane (2,2-DCP). An automated headspace technique using gas chromatography was developed to determine rates of metabolism. Additional dihaloalkanes (1,2-dichloroethane, 1,2-dichloropropane, 1,4-dichlorobutane, 1,2-dibromoethane, 1,2-dibromopropane, 1,4-dibromobutane) were evaluated to assess structure-activity relationships. In general, brominated dihaloalkanes were eliminated from rat cytosol faster than chlorinated dihaloalkanes, reflecting the expected halide order of reactivity (Br > Cl). Furthermore, the rate of GSH conjugation was proportional to alpha,omega-haloalkane chain length. The clearance of 1,3-DCP via the GSH conjugation pathway (1.6 x 10(-4) l/h/mg cytosol protein) was minor relative to the P450 pathway (2.8 x 10(-2) l/h/mg microsomal protein). In contrast, we did not observe metabolism of 2,2-DCP via the GSH-dependent conjugation pathway and observed only a minor level of clearance via the P450 pathway (7 x 10(-4) l/h/mg microsomal protein). Neither compound was mutagenic in various strains of Salmonella, including those containing GSTT1-1, indicating that GSTT1-1 does not metabolize 1,3-DCP or 2,2-DCP to mutagens. Analysis of the reaction products of 1,3-DCP and GSH in cytosol by liquid chromatography/mass spectrometry revealed significant production of S-(3-chloropropyl) glutathione conjugate, indicating that the conjugate half-mustard does not rearrange to form a sulfonium ion, as typically occurs with vicinal dihaloalkanes.
authors.affiliation: Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, USA. tornero-velez.rogelio@epa.gov
authors.forename: Rogelio
authors.initials: R
authors.lastname: Tornero-Velez
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Ross
authors.forename: Courtney
authors.initials: C
authors.lastname: Granville
authors.forename: John
authors.initials: J
authors.lastname: Laskey
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Jones
authors.forename: David M
authors.initials: DM
authors.lastname: DeMarini
authors.forename: Marina V
authors.initials: MV
authors.lastname: Evans
mesh_terms: D000818:Animals; D002849:Chromatography, Gas; D003600:Cytosol / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D005978:Glutathione / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D015233:Models, Statistical; D009152:Mutagenicity Tests; D009153:Mutagens / Q000378:metabolism* / Q000633:toxicity*; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D011407:Propane / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D012475:Salmonella / Q000235:genetics / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D014162:Transfection; D014874:Water Pollutants, Chemical / Q000378:metabolism* / Q000633:toxicity*
chemical_list: D018076:DNA, Complementary; D009153:Mutagens; D014874:Water Pollutants, Chemical; D009249:NADP; C067434:1,3-dichloropropane; C489646:2,2-dichloropropane; D005978:Glutathione; D011407:Propane