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The roles of glutathione s-transferase theta 1-1 and cytochrome P450 2E1 in the metabolism and genotoxicity of the water disinfection byproduct bromodichloromethane in human urothelial cells
Citation:
Patullo, C., S. Simmons, A. Teal, AND R. Pegram. The roles of glutathione s-transferase theta 1-1 and cytochrome P450 2E1 in the metabolism and genotoxicity of the water disinfection byproduct bromodichloromethane in human urothelial cells. NC SOT, Research Triangle Park, NC, October 07, 2019. https://doi.org/10.23645/epacomptox.22572613
Impact/Purpose:
This presentation provides initial data addressing the roles of xenobiotic metabolizing enzymes in potential carcinogenic mechanisms of the drinking water disinfection byproducts, brominated trihalomethanes, in the human bladder.
Description:
Exposure to disinfection byproducts (DBPs) via drinking water has been associated with an increased risk for bladder cancer in many epidemiology studies. Trihalomethanes (THMs) are drinking water DBPs formed during the chlorination of water by reactions of chlorine species and organic carbon. Bromodichloromethane (BDCM), a brominated THM, is metabolized via two key pathways: mutagenic activation by glutathione S-transferase theta 1-1 (GSTT1-1) and oxidation by cytochrome P450 2El (CYP2E1). Our research focuses on the genotoxicity of BDCM in human urothelial cells when metabolized via GSTT1-1 as well as determining which enzyme is more active in the human bladder to help better understand potential carcinogenic effects of BDCM related to bladder cancer. First, we used the cytokinesis-block micronucleus assay to measure DNA damage by BDCM and the effect of GSTT1-1 overexpression in SV-HUC-1 cells, a cell line derived from normal human urothelial cells. We also performed a spectrophotometric analysis of GSTT1-1 and CYP2E1 activity in SV-HUC-1 cells and compared the data to either normal human or mouse hepatic cells. Dose-dependent increases in DNA damage were observed when SV-HUC-1 cells were dosed with BDCM and these were further increased by GSTT1-1 overexpression. Additionally, we found that GSTT1-1 activity was higher in human urothelial cells than human hepatic cells. The opposite was observed regarding CYP2E1 activity; the activity of CYP2E1 was much lower in human bladder cells than in mouse hepatic cells. This suggests that brominated THM metabolism by GSTT1-1 in human bladder cells is likely, which may be a factor in the DBP-associated increased risk for bladder cancer. (This abstract does not reflect U.S. EPA policy.)
URLs/Downloads:
DOI: The roles of glutathione s-transferase theta 1-1 and cytochrome P450 2E1 in the metabolism and genotoxicity of the water disinfection byproduct bromodichloromethane in human urothelial cells
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