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DOI10.1155/2015/764375
Kinetic Modeling Reveals the Roles of Reactive Oxygen Species Scavenging and DNA Repair Processes in Shaping the Dose-Response Curve of KBrO3-Induced DNA Damage
Spassova, Maria A.1; Miller, David J.2; Nikolov, Alexander S.3
发表日期2015
ISSN1942-0900
英文摘要

We have developed a kinetic model to investigate how DNA repair processes and scavengers of reactive oxygen species (ROS) can affect the dose-response shape of prooxidant induced DNA damage. We used as an example chemical KBrO3 which is activated by glutathione and forms reactive intermediates that directly interact with DNA to form 8-hydroxy-2-deoxyguanosine DNA adducts (8-OH-dG). The single strand breaks (SSB) that can result from failed base excision repair of these adducts were considered as an effect downstream from 8-OH-dG. We previously demonstrated that, in the presence of effective base excision repair, 8-OH-dG can exhibit threshold-like dose-response dependence, while the downstream SSB can still exhibit a linear dose-response. Here we demonstrate that this result holds for a variety of conditions, including low levels of GSH, the presence of additional SSB repair mechanisms, or a scavenger. It has been shown that melatonin, a terminal scavenger, inhibits KBrO3-caused oxidative damage. Our modeling revealed that sustained exposure to KBrO3 can lead to fast scavenger exhaustion, in which case the dose-response shapes for both endpoints are not substantially affected. The results are important to consider when forming conclusions on a chemical's toxicity dose dependence based on the dose-response of early genotoxic events.


语种英语
WOS记录号WOS:000361664000001
来源期刊OXIDATIVE MEDICINE AND CELLULAR LONGEVITY
来源机构美国环保署
文献类型期刊论文
条目标识符http://gcip.llas.ac.cn/handle/2XKMVOVA/59054
作者单位1.US EPA, Natl Ctr Environm Assessment, Off Res & Dev, Washington, DC 20460 USA;
2.NCI, Div Canc Biol, NIH, Rockville, MD 20892 USA;
3.Langley High Sch, Mclean, VA 22101 USA
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Spassova, Maria A.,Miller, David J.,Nikolov, Alexander S.. Kinetic Modeling Reveals the Roles of Reactive Oxygen Species Scavenging and DNA Repair Processes in Shaping the Dose-Response Curve of KBrO3-Induced DNA Damage[J]. 美国环保署,2015.
APA Spassova, Maria A.,Miller, David J.,&Nikolov, Alexander S..(2015).Kinetic Modeling Reveals the Roles of Reactive Oxygen Species Scavenging and DNA Repair Processes in Shaping the Dose-Response Curve of KBrO3-Induced DNA Damage.OXIDATIVE MEDICINE AND CELLULAR LONGEVITY.
MLA Spassova, Maria A.,et al."Kinetic Modeling Reveals the Roles of Reactive Oxygen Species Scavenging and DNA Repair Processes in Shaping the Dose-Response Curve of KBrO3-Induced DNA Damage".OXIDATIVE MEDICINE AND CELLULAR LONGEVITY (2015).
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