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首页> 外文期刊>The Journal of Steroid Biochemistry and Molecular Biology >Characterization of the 'estrogenicity' of tamoxifen and raloxifene in HepG2 cells: regulation of gene expression from an ERE controlled reporter vector versus regulation of the endogenous SHBG and PS2 genes.
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Characterization of the 'estrogenicity' of tamoxifen and raloxifene in HepG2 cells: regulation of gene expression from an ERE controlled reporter vector versus regulation of the endogenous SHBG and PS2 genes.

机译:他莫昔芬和雷洛昔芬在HepG2细胞中的“雌激素性”特征:ERE调控的报告载体对基因表达的调控与内源性SHBG和PS2基因的调控。

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摘要

The estrogenic character of tamoxifen and raloxifene was studied on three different genes, an ERE-reporter construct and two endogenous genes, sex hormone binding globulin (SHBG) and pS2, in two variants of the human liver carcinoma cell line HepG2. On the ERE-reporter construct and the pS2 gene both tamoxifen and raloxifene acted as pure estrogen antagonists, whereas on the SHBG gene they functioned as partial estrogens/antiestrogens at concentrations below 1 microM and as full "agonists" at concentrations higher than 1 microM. The fold stimulatory effect of tamoxifen and raloxifene on SHBG protein expression was similar in the estrogen receptor (ER) expressing HepG2 cells (HepER3) and the parental non-ER expressing HepG2 cells at concentrations above 1 microM. In contrast, the 17beta-estradiol analogue moxestrol stimulated SHBG expression only in the HepER3 cells. Both tamoxifen and raloxifene had an additive effect to estrogen receptor-dependent SHBG gene expression in the HepER3 cells in the presence of saturating concentrations of moxestrol. However, a significant difference was observed in that a much higher concentration of moxestrol was required to see an additive effect of raloxifene compared to tamoxifen. The cytokine IL1-beta completely blocked the tamoxifen-dependent induction of SHBG gene expression in HepER3 cells, but only partly blocked the effect of moxestrol mediated by the ER. In conclusion, our results suggest that the mechanism for the liver-selective "estrogenic" character of tamoxifen and raloxifene is mediated by a non-ER dependent pathway.
机译:在人类肝癌细胞系HepG2的两个变体中,在三个不同的基因上研究了他莫昔芬和雷洛昔芬的雌激素特性,这些基因是ERE报告基因构建体和两个内源性基因,即性激素结合球蛋白(SHBG)和pS2。在ERE-报告基因构建体和pS2基因上,他莫昔芬和雷洛昔芬均充当纯雌激素拮抗剂,而在SHBG基因上,它们充当浓度低于1 microM的部分雌激素/抗雌激素和浓度高于1 microM的完全“激动剂”。他莫昔芬和雷洛昔芬对SHBG蛋白表达的倍数刺激作用在浓度高于1 microM的雌激素受体(ER)表达的HepG2细胞(HepER3)和亲本非ER表达的HepG2细胞中相似。相比之下,17β-雌二醇类似物莫雌酚仅在HepER3细胞中刺激SHBG表达。他莫昔芬和雷洛昔芬都对饱和浓度莫昔洛尔在HepER3细胞中依赖雌激素受体的SHBG基因表达有加和作用。但是,观察到一个显着差异,即与他莫昔芬相比,要达到雷洛昔芬的加和作用,需要更高浓度的莫西雌酚。细胞因子IL1-β完全阻断HepER3细胞中他莫昔芬依赖性SHBG基因表达的诱导,但仅部分阻断ER介导的莫西雌酚的作用。总之,我们的结果表明,他莫昔芬和雷洛昔芬对肝脏具有选择性的“雌激素性”特征的机制是由非ER依赖性途径介导的。

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