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METABOLISM AND MUTAGENICITY OF SOURCE WATER CONTAMINANTS 1, 3-DICHLOROPROPANE AND 2,2-DICHLOROPROPANE
Citation:
TORNERO-VELEZ, R., M. K. Ross, C. A. Granville, J. Laskey, J. P. Jones, D M. DeMarini, AND M V. Evans. METABOLISM AND MUTAGENICITY OF SOURCE WATER CONTAMINANTS 1, 3-DICHLOROPROPANE AND 2,2-DICHLOROPROPANE. DRUG METABOLISM AND DISPOSITION 32(1):123-131, (2003).
Description:
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. EPA Contaminant Candidate List (CCL), 1,3-dichloropropane (1,3-DCP) and 2,2-dichloropropane (2,2-DCP). An automated equilibrium headspace technique utilizing gas chromatography was developed to determine rates of metabolism of these volatile chemicals. 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 with GSH (Br>Cl). Furthermore, the rate of GSH conjugation was proportional to a,w-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; Vmax= 30.3 nmol/h/mg microsomal protein, Km=1.09 M). In contrast to 1,3-DCP, 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 (7x10-4 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 mixture of 1,3-DCP and GSH in cytosol by LC-MS revealed significant production of S-(3-chloropropyl) glutathione conjugate, indicating that the conjugate half-mustard does not rearrange to form an sulfonium ion, as typically occurs with vicinal dihaloalkanes such as 1,2-dichloroethane.