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COMPARISON OF DETOXIFICATION AND BIOACTIVATION PATHWAYS FOR BROMODICHLOROMETHANE IN THE RAT
Citation:
Ross, M. K., C R. Eklund, AND R A. Pegram. COMPARISON OF DETOXIFICATION AND BIOACTIVATION PATHWAYS FOR BROMODICHLOROMETHANE IN THE RAT. Presented at Society of Toxicology, Baltimore, MD, March 21-25, 2004.
Description:
Comparison of Detoxification and Bioactivation pathways FOR Bromodichloromethane in the Rat
M.K. Ross1, C.R. Eklund2, and R.A. Pegram2
1Curriculum in Toxicology, UNC-CH, Chapel Hill, NC
2ETD, NHEERL/ORD, USEPA, Research Triangle Park, NC
Bromodichloromethane (BDCM) is metabolized via high- (CYP2E1) and low- (GSTT1) affinity pathways. The CYP2E1 pathway is thought to be a detoxification pathway at low hepatic concentrations. The GST pathway produces a labile genotoxic intermediate that is unlikely to escape from within cells where it is formed. Evidence for GSTT1-specific metabolism of BDCM is supported by experiments which demonstrate that co-incubation of BDCM competitively inhibits GSTT1 activity toward the model substrate 1,2-epoxy-3-(4?-nitrophenoxy)propane (ENPP) (Kic = 4.2?0.5 mM). The flux of BDCM through the CYP2E1- and GSTT1-pathways has been investigated in vitro in non-target (liver) and cancer target tissues (kidney and large intestine) of the F344 rat. Compared to the liver, the intrinsic clearance (Vmax/Km) of BDCM via CYP-metabolism in target tissues was significantly reduced (8- and 16-fold for kidney and large intestine, respectively) while GST-metabolism in the same tissues was only slightly lower (~2?3-fold), suggesting less efficient detoxification particularly at high tissue concentrations of BDCM that saturate CYP2E1. The kinetic parameters of GSTT1-1 metabolism in liver and kidney have been incorporated into a previously published rat PBPK model for BDCM developed from this laboratory. Model simulations following constant inhaled exposures to BDCM indicate that CYP is the dominant pathway in liver and kidney following low inhaled concentrations; however, at high inhaled concentrations, the flux through CYP2E1 in kidney becomes saturated and the GSTT1-1 pathway becomes more pronounced than CYP in terms of total flux (at 3200 ppm, 235 mg BDCM metabolized by CYP2E1/liter per 6 h compared with 265 mg BDCM metabolized by GST/liter per 6 h). Model simulations of oral doses in the dose range used in the cancer bioassay study do not result in saturation of hepatic or kidney CYP2E1 and thus flux through the GST pathway is limited. The model simulations suggest that greater genotoxic outcomes from BDCM exposure may occur from the inhalation route rather than the oral route. (Abstract does not reflect USEPA policy. Supported by F32 ES11111-01).