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BROMODICHLOROMETHANE TOXICOKINETICS: LINKING METABOLISM TO EFFECT
Citation:
Pegram, R A., M. K. Ross, A B. DeAngelo, J W. Allis, AND G. Zhao. BROMODICHLOROMETHANE TOXICOKINETICS: LINKING METABOLISM TO EFFECT. Presented at Society of Toxicology 42nd Annual Meeting, Salt Lake City, Utah, March 9-13, 2003.
Description:
Bromodichloromethane (BDCM), a trihalomethane (THM), is among the most prevalent disinfection byproducts found in chlorinated drinking water. Weak associations between THM exposure and cancers of the bladder and lower GI tract have been suggested by positive epidemiological studies of chlorinated drinking water exposures in humans. Chronic high-dose
administration of BDCM to rodents induced kidney and colon carcinomas. A series of in vivo and in vitro studies have been undertaken to evaluate the toxicokinetics and effects of BDCM. BDCM is metabolized by cytochrome P-450 isozymes and by cytosolic glutathione S-transferase theta 1-1 (GST T1-1). CYP2E1 is the principal metabolizing enzyme in both humans and rats,
and the in vitro metabolic parameters for recombinant preparations of human and rat CYP2E1 were almost identical. We have found that CYP1A2 metabolizes BDCM, and can now report a lower Km for the human enzyme compared to its rat counterpart. BDCM is also metabolized to a mutagenic intermediate(s) via GST T1-1. The relative mutagenic potency of the four THMs correlates well with their relative potency as inducers of preneoplastic aberrant crypt foci in the rat large intestine. GST T1-1 is the primary catalyst for BDCM-glutathione conjugation, leading to product(s) that covalently modify DNA and form deoxyguanosine adducts in vitro, consistent with previous observations of GST T1-1-dependent mutagenicity of BDCM. Additional metabolites of this pathway were identified, including S-formyl-GSH and formate. Comparison of the catalytic efficiencies of CYP2E1- and GST T1-1-mediated BDCM metabolism indicate that GST-dependent metabolism is a quantitatively minor pathway, but glutathione conjugation may give rise to extremely reactive intermediates that induce disproportionately toxic responses. Tissues (kidney and colon) that have higher ratios of GST T1-1:CYP2E1 activities are targets for
BDCM-induced carcinoma in rats. (MK Ross and G Zhao were supported by UNC/EPA Cooperative Training Agreement CT827206. This abstract does not necessarily reflect EPA policy.)