| Cellular and molecular mechanisms of bromate-induced cytotoxicity in human and rat kidney cells. | |
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MedLine Citation:
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PMID: 20067818 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The mechanisms of bromate (BrO(3)(-))-induced toxicity in Normal Rat Kidney (NRK) and human embryonic kidney 293 (HEK293) cells were investigated. BrO(3)(-) (added as KBrO(3)) induced concentration-dependent decreases in 3-(4, dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) staining after 48 h. BrO(3)(-)-induced necrosis based on tandem increases in annexin V and PI staining. Cell cycle analysis demonstrated that BrO(3)(-) also induced G2/M arrest and nuclear fragmentation, prior to alterations in MTT staining or annexin V and PI staining. Immunoblot analysis demonstrated that the G2/M arrest correlated to induction of phosphorylated (p)-p53, p21, cyclin B1 and p-cdc2. Further, BrO(3)(-) induced time-dependent increases in the activity of the mitogen activated protein kinases p38 and ERK1/2. Treatment of cells with the p38 inhibitor SB202190, but not the ERK1/2 inhibitor PD98059, partially reversed BrO(3)(-)-induced G2/M arrest and decreased BrO(3)(-)-induced p-p53, p21 and cyclin B1 expression. In addition, BrO(3)(-) treatment induced reactive oxygen species (ROS) based on increases in CM-H(2)DCFDA fluorescence. The antioxidant ascorbic acid inhibited BrO(3)(-)-induced p38 activation, G2/M arrest, p-p53, p21 and cyclin B1 expression; however, ascorbic acid had no effect on BrO(3)(-)-induced formation of 8-OHdG, a marker of DNA oxidative damage, whose increases preceded cell death by 24h. These data suggest that ROS mediated MAPK activation is involved in the molecular mechanisms of BrO(3)(-)-induced cell cycle arrest, which occurs independently of 8-OH-dG production. The similar mode of action in both NRK and HEK293 cells suggests that the mechanisms of BrO(3)(-)-induced renal cell death are model-independent. |
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Authors:
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Xiaoling Zhang; Dilhara De Silva; Bin Sun; Jeffery Fisher; Richard J Bull; Joseph A Cotruvo; Brian S Cummings |
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Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't Date: 2010-01-11 |
Journal Detail:
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Title: Toxicology Volume: 269 ISSN: 1879-3185 ISO Abbreviation: Toxicology Publication Date: 2010 Feb |
Date Detail:
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Created Date: 2010-02-22 Completed Date: 2010-03-18 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0361055 Medline TA: Toxicology Country: Ireland |
Other Details:
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Languages: eng Pagination: 13-23 Citation Subset: IM |
Copyright Information:
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(c) 2010 Elsevier Ireland Ltd. All rights reserved. |
Affiliation:
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Department of Pharmaceutical and Biomedical Sciences, 336 Pharmacy South, College of Pharmacy, University of Georgia, Athens, GA 30602, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Bromates / toxicity* Cell Cycle / drug effects*, physiology Cell Line Humans Kidney / drug effects*, pathology*, physiology Rats |
| Chemical | |
Reg. No./Substance:
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0/Bromates; 7758-01-2/potassium bromate |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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