Dichlorodiphenyldichloroethylene exposure reduces r-GCS via suppressed Nrf2 in HepG2 cells

Xiaoting Jin, Li Song (Lead / Corresponding author), Zhuoyu Li, Ian P. Newton, Meirong Zhao, Weiping Liu

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    9 Citations (Scopus)


    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.

    Original languageEnglish
    Pages (from-to)350-359
    Number of pages10
    JournalEnvironmental Toxicology
    Issue number3
    Early online date29 Sept 2014
    Publication statusPublished - 1 Mar 2016


    • HepG2
    • NF-E2-related factor 2
    • p,p′-dichlorodiphenyldichloroethylene
    • Reactive oxygen species
    • γ-glutamyl-cysteine synthetase

    ASJC Scopus subject areas

    • Health, Toxicology and Mutagenesis
    • Toxicology
    • Management, Monitoring, Policy and Law


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