• estradiol;
  • idoxifene;
  • IκB-α;
  • NF-κB;
  • oxidative stress;
  • pyrrolidine dithiocarbamate;
  • selective estrogen receptor modulator

Abstract:Background/Aims: Idoxifene is a tissue-specific selective estrogen receptor modulator. Estradiol is a potent endogenous antioxidant, and nuclear factor κB (NF-κB) is a key transcription factor that induces multiple genes in response to inflammation or oxidative stress. The aim of this study was to explore the inhibitory effects of idoxifene and estradiol on NF-κB activation in hepatocytes in a state of oxidative stress. Methods: Lipid peroxidation was induced in cultured rat hepatocytes by incubation with ferric nitrilotriacetate solution. NF-κB activity was evaluated by electrophoretic mobility shift assay. Results: The oxidative stress-induced activation of NF-κB and degradation of IκB-α were maximal at 3–5 h, with an increase in lactate dehydrogenase (LDH) and malondialdehyde (MDA) secretion into the culture medium. Treatment with idoxifene and estradiol inhibited IκB-α degradation and NF-κB activation through the attenuation of hepatocyte oxidative bursts and decreased extracellular levels of LDH and MDA. In addition, idoxifene and estradiol inhibited lipid peroxidation in rat liver mitochondria. A potent NF-κB inhibitor, pyrrolidine dithiocarbamate, prevented NF-κB activation by inhibition of IκB-α degradation and decreased LDH and MDA levels, suggesting that NF-κB might be a regulator in a genetic response to increase oxidative stress-induced hepatic injury. Conclusions: These findings suggest that idoxifene and estradiol function as antioxidants and protect hepatocytes from inflammatory cell injury.