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

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. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 350–359, 2016.