title: Idoxifene and estradiol enhance antiapoptotic activity through estrogen receptor-beta in cultured rat hepatocytes.
abstract: Oxidative stress plays a causative role in the development of hepatic fibrosis and apoptosis. Estradiol (E2) is an antioxidant, and idoxifene is a tissue-specific selective estrogen-receptor modulator. We have previously demonstrated that E2 inhibits hepatic fibrosis in rat models of hepatic fibrosis and that the actions of E2 are mediated through estrogen receptors (ERs). This study reports on the antiapoptotic role of idoxifene and E2, and the functions of ER subtypes ER-alpha and ER-beta in hepatocytes undergoing oxidative stress. Lipid peroxidation was induced in cultured rat hepatocytes with ferric nitrilotriacetate solution with idoxifene or E2. Oxidative stress-induced early apoptosis was linked to its ability to inhibit not only the expression of Bcl-2 and Bcl-XL but the production of antioxidant enzymes as well and to stimulate Bad expression. Hepatocytes possessed functional ER-beta, but not ER-alpha, to respond directly to idoxifene and E2. Idoxifene and E2 suppressed oxidative stress-induced reactive oxygen species generation and lipid peroxidation, and their antiapoptotic effects on the activation of activator protein-1 and nuclear factor-kappaB, the loss of antioxidant enzyme activity, and Bcl-2 family protein expression in early apoptotic hepatocytes were blocked by the pure ER antagonist ICI 182,780. Our results indicate that idoxifene and E2 could enhance antiapoptotic activity through ER-beta during oxidative damage in hepatocytes.
authors.affiliation: Department of Digestive and Cardiovascular Medicine, Tokushima University School of Medicine, Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
authors.forename: Ichiro
authors.initials: I
authors.lastname: Shimizu
authors.forename: Guangming
authors.initials: G
authors.lastname: Lu
authors.forename: Mina
authors.initials: M
authors.lastname: Itonaga
authors.forename: Xuezhi
authors.initials: X
authors.lastname: Cui
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Okamura
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shono
authors.forename: Hirohito
authors.initials: H
authors.lastname: Honda
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
authors.forename: Masami
authors.initials: M
authors.lastname: Muramatsu
authors.forename: Susumu
authors.initials: S
authors.lastname: Ito
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D002478:Cells, Cultured; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D047629:Estrogen Receptor beta; D005260:Female; D005434:Flow Cytometry; D000077267:Fulvestrant; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000503:physiopathology; D008297:Male; D018613:Microscopy, Confocal; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D011960:Receptors, Estrogen / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D004965:Estrogen Antagonists; D047629:Estrogen Receptor beta; D011960:Receptors, Estrogen; D013629:Tamoxifen; D000077267:Fulvestrant; C071362:idoxifene; D004958:Estradiol