title: Glutathione-mediated detoxification of halobenzoquinone drinking water disinfection byproducts in T24 cells.
abstract: Halobenzoquinones (HBQs) are a new class of drinking water disinfection byproducts (DBPs) and are capable of producing reactive oxygen species and causing oxidative damage to proteins and DNA in T24 human bladder carcinoma cells. However, the exact mechanism of the cytotoxicity of HBQs is unknown. Here, we investigated the role of glutathione (GSH) and GSH-related enzymes including glutathione S-transferase (GST) and glutathione peroxidase (GPx) in defense against HBQ-induced cytotoxicity in T24 cells. The HBQs are 2,6-dichloro-1,4-benzoquinone (DCBQ), 2,6-dichloro-3-methyl-1,4-benzoquinone (DCMBQ), 2,3,6-trichloro-1,4-benzoquinone (TriCBQ), and 2,6-dibromobenzoquinone (DBBQ). We found that depletion of cellular GSH could sensitize cells to HBQs and extracellular GSH supplementation could attenuate HBQ-induced cytotoxicity. HBQs caused significant cellular GSH depletion and increased cellular GST activities in a concentration-dependent manner. Our mass spectrometry study confirms that HBQs can conjugate with GSH, explaining in part the mechanism of GSH depletion by HBQs. The effects of HBQs on GPx activity are compound dependent; DCMBQ and DBBQ decrease cellular GPx activities, whereas DCBQ and TriCBQ have no significant effects. Pearson correlation analysis shows that the cellular GSH level is inversely correlated with ROS production and cellular GST activity in HBQ-treated cells. These results support a GSH and GSH-related enzyme-mediated detoxification mechanism of HBQs in T24 cells.
authors.affiliation: Division of Analytical and Environmental Toxicology, Department of Laboratory Medicine and Pathology, University of Alberta, 10-102 Clinical Sciences Building, Edmonton, Alberta, Canada T6G 2G3.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Li
authors.affiliation: Division of Analytical and Environmental Toxicology, Department of Laboratory Medicine and Pathology, University of Alberta, 10-102 Clinical Sciences Building, Edmonton, Alberta, Canada T6G 2G3.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Division of Analytical and Environmental Toxicology, Department of Laboratory Medicine and Pathology, University of Alberta, 10-102 Clinical Sciences Building, Edmonton, Alberta, Canada T6G 2G3.
authors.forename: Hongquan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Division of Analytical and Environmental Toxicology, Department of Laboratory Medicine and Pathology, University of Alberta, 10-102 Clinical Sciences Building, Edmonton, Alberta, Canada T6G 2G3.
authors.forename: X Chris
authors.initials: XC
authors.lastname: Le
authors.affiliation: Division of Analytical and Environmental Toxicology, Department of Laboratory Medicine and Pathology, University of Alberta, 10-102 Clinical Sciences Building, Edmonton, Alberta, Canada T6G 2G3 xingfang.li@ualberta.ca.
authors.forename: Xing-Fang
authors.initials: XF
authors.lastname: Li
mesh_terms: D016227:Benzoquinones / Q000378:metabolism* / Q000633:toxicity; D045744:Cell Line, Tumor; D004202:Disinfectants / Q000378:metabolism* / Q000633:toxicity; D004203:Disinfection; D004305:Dose-Response Relationship, Drug; D060766:Drinking Water; D005978:Glutathione / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D008658:Inactivation, Metabolic; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000378:metabolism*; D014874:Water Pollutants, Chemical / Q000378:metabolism* / Q000633:toxicity; D018508:Water Purification; D014881:Water Supply
chemical_list: D016227:Benzoquinones; D004202:Disinfectants; D060766:Drinking Water; D017382:Reactive Oxygen Species; D014874:Water Pollutants, Chemical; C071926:2,6-dichlorobenzoquinone; D005979:Glutathione Peroxidase; D005982:Glutathione Transferase; D005978:Glutathione
keywords: disinfection byproducts; glutathione; glutathione S-transferase; glutathione peroxidase; halobenzoquinones