T Omoya1, I Shimizu, Y Zhou, Y Okamura, H Inoue, G Lu, M Itonaga, H Honda, M Nomura, S Ito. 1. Second Department of Internal Medicine, Tokushima University School of Medicine, Tokushima, and General Laboratory for Medical Research, Tokushima University School of Medicine, Tokushima, Japan.
Abstract
BACKGROUND/AIMS: Idoxifene is a tissue-specific selective estrogen receptor modulator. Estradiol is a potent endogenous antioxidant, and nuclear factor kappaB (NF-kappaB) 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-kappaB 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-kappaB activity was evaluated by electrophoretic mobility shift assay. RESULTS: The oxidative stress-induced activation of NF-kappaB and degradation of IkappaB-alpha 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 IkappaB-alpha degradation and NF-kappaB 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-kappaB inhibitor, pyrrolidine dithiocarbamate, prevented NF-kappaB activation by inhibition of IkappaB-alpha degradation and decreased LDH and MDA levels, suggesting that NF-kappaB 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.
BACKGROUND/AIMS: Idoxifene is a tissue-specific selective estrogen receptor modulator. Estradiol is a potent endogenous antioxidant, and nuclear factor kappaB (NF-kappaB) 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-kappaB 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-kappaB activity was evaluated by electrophoretic mobility shift assay. RESULTS: The oxidative stress-induced activation of NF-kappaB and degradation of IkappaB-alpha 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 IkappaB-alpha degradation and NF-kappaB 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-kappaB inhibitor, pyrrolidine dithiocarbamate, prevented NF-kappaB activation by inhibition of IkappaB-alpha degradation and decreased LDH and MDA levels, suggesting that NF-kappaB 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.
Authors: T Itagaki; I Shimizu; X Cheng; Y Yuan; A Oshio; K Tamaki; H Fukuno; H Honda; Y Okamura; S Ito Journal: Gut Date: 2005-12 Impact factor: 23.059
Authors: Whitney M Ellefson; Ashley M Lakner; Alicia Hamilton; Iain H McKillop; Herbert L Bonkovsky; Nury M Steuerwald; Yvette M Huet; Laura W Schrum Journal: PLoS One Date: 2011-12-20 Impact factor: 3.240