title: Dichlorodiphenyldichloroethylene exposure reduces r-GCS via suppressed Nrf2 in HepG2 cells.
abstract: p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE), the major isomer of persistent 1,1-Bis(4-chlorophenyl)-2,2,2-trichloroethane metabolite, is highly associated with the risk of liver cancer. γ-glutamyl-cysteine synthetase (γ-GCS), which is the rate-limiting enzyme of glutathione (GSH) biosynthesis and an important scavenger of reactive oxygen species (ROS), is considered as a potential therapeutic target for many cancers. However, the association between the body burden of p,p'-DDE and γ-GCS has not been fully established. Here, we indicated that low doses of p,p'-DDE exposure promoted the proliferation and decreased γ-GCS activity of HepG2 cells in a dose- and time-dependent manner. In addition, p,p'-DDE elevated ROS content and attenuated glutathione peroxidase activity. This was accompanied with inhibitions of NF-E2-related factor 2 (Nrf2) at the mRNA and protein levels. ROS inhibitor supplement could significantly reverse these effects. Moreover, the addition of the proteasome inhibitor, MG132, strongly reversed the p,p'-DDE-reduced Nrf2 expression and γ-GCS activity. Consistently, GSH content was in line with the alteration of γ-GCS. Collectively, the results indicate that p,p'-DDE treatment downregulates γ-GCS activity in HepG2 cells by inducing ROS-mediated Nrf2 loss.
authors.affiliation: Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan, 030006, China.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Jin
authors.affiliation: Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan, 030006, China.|MOE Key Lab of Environmental Remediation and Ecosystem Health, College of Environmental and Resource Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, China.
authors.forename: Li
authors.initials: L
authors.lastname: Song
authors.affiliation: Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan, 030006, China.|College of Life Science, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
authors.forename: Zhuoyu
authors.initials: Z
authors.lastname: Li
authors.affiliation: Division of Cell & Developmental Biology, College of Life Sciences, University of Dundee, Dundee, DD15EH, Scotland, UK.
authors.forename: Ian P
authors.initials: IP
authors.lastname: Newton
authors.affiliation: Research Center of Environmental Science, Zhejiang University of Technology, Hangzhou, 310032, China.
authors.forename: Meirong
authors.initials: M
authors.lastname: Zhao
authors.affiliation: MOE Key Lab of Environmental Remediation and Ecosystem Health, College of Environmental and Resource Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, China.
authors.forename: Weiping
authors.initials: W
authors.lastname: Liu
mesh_terms: D003633:Dichlorodiphenyl Dichloroethylene / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005721:Glutamate-Cysteine Ligase / Q000235:genetics* / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000378:metabolism / Q000502:physiology*; D059748:Proteolysis / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D003633:Dichlorodiphenyl Dichloroethylene; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione
keywords: HepG2; NF-E2-related factor 2; p,p′-dichlorodiphenyldichloroethylene; reactive oxygen species; γ-glutamyl-cysteine synthetase