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EVIDENCE FOR BROMODICHLOROMETHANE METABOLISM BY CYTOCHROME P-450 1A2
Citation:
Ross, T. M., B. P. Anderson, R A. Pegram, J W. Allis, AND G. Zhao. EVIDENCE FOR BROMODICHLOROMETHANE METABOLISM BY CYTOCHROME P-450 1A2. Presented at SOT, San Francisco, CA, March 25-29,2001.
Description:
EVIDENCE FOR BROMODICHLOROMETHANE METABOLISM BY CYTOCHROME P-450 1A2. T M Ross1, B P Anderson1, G Zhao2, R A Pegram1 and J W Allis1. 1U.S. EPA, ORD, NHEERL, Research Triangle Park, NC; 2University of North Carolina, Chapel Hill, NC.
Sponsor: H Barton
Bromodichloromethane (BDCM) is a prevalent chlorination by-product in drinking water that has been shown to cause acute liver and kidney toxicity as well as cancers of the liver, kidney, and large intestine in laboratory animals. Although BDCM is primarily metabolized by CYP2E1, previous work from our laboratory demonstrated that CYP1A can be inhibited by BDCM and may therefore play a role in its metabolism. In the present study, groups of F344 rats aged 90 d were pretreated 3 d prior to BDCM dosing with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (1.0 g/kg body wt, p.o.) to induce CYP1A1/2 without inducing CYP2E1 or CYP2B1/2. In one of the CYP1A1/2-induced groups, isosafrole (ISO) was administered (162 mg/kg, i.p.) 30 min prior to BDCM dosing to inhibit CYP1A2. Three CYP1A1/2-induced groups were then dosed orally with either 0, 200 or 400 mg BDCM/kg body wt; the TCDD+ISO group was given 400 mg BDCM/kg, and the control group was neither pretreated nor dosed with BDCM. A 41% decrease in CYP1A2-catalyzed methoxyresorufin-O-demethylase activity was observed in TCDD+ISO-treated rats compared to the TCDD groups, but other CYP activities were not decreased by ISO. To assess total metabolism of BDCM at 24 hr after BDCM dosing, plasma bromide ion concentrations were determined using an ion-specific electrode. Plasma bromide increased with BDCM dose in the CYP1A1/2-induced rats, but at 400 mg BDCM/kg, bromide in the TCDD+ISO-treated group was 47% less than in the TCDD group. The severity of acute hepatotoxicity, as indicated by serum sorbitol dehydrogenase (SDH) levels, paralleled the metabolism data. In the group treated with TCDD+ISO and dosed with 400 mg BDCM/kg, the serum SDH level was 52% less than that observed in the TCDD group receiving the same BDCM dose. The clear correlations between CYP1A2 modulation, BDCM metabolism, and liver toxicity demonstrate that CYP1A2 metabolizes BDCM, producing a hepatotoxic intermediate. (This abstract does not reflect EPA policy.)