Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds on the occupied nuclear estrogen receptor in MCF-7 human breast cancer cells.
Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds on the occupied nuclear estrogen receptor in MCF-7 human breast cancer cells.
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发表时间：
1990-06
期刊：
影响因子：
11.2
通讯作者：
M. Harris;T. Zacharewski;S. Safe
中科院分区：
文献类型：
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作者：
M. Harris;T. Zacharewski;S. Safe
用17 β-[3H]雌二醇处理MCF-7人乳腺癌细胞，导致细胞核雌激素受体复合物迅速聚集，在1小时内达到最大值，3小时后下降。在加入放射性标记的激素之前6或12小时用2，3，7，8-四氯二苯并-对-二恶英（TCDD）预处理细胞，分别导致占据的核雌激素受体水平降低38%和63%，而在放射性配体前1h加入TCDD，用速度沉降法测定，未引起核受体的水平发生任何显著变化分析.此外，雌激素受体抗体也显示，在10（-8）至10（-11）M TCDD浓度下，TCDD介导的占据核受体水平的剂量依赖性降低被免疫反应蛋白的类似降低所抵消。细胞核雌激素受体水平的降低不是由于雌二醇代谢增加，因为在MCF-7细胞中，在不诱导细胞色素P-450依赖性单加氧酶活性的TCDD浓度（10（-11）至10（-13）M）下观察到显著降低。用放线菌素D或环己酰亚胺处理MCF-7细胞，导致所占用的核雌激素受体水平增加2倍以上，而用TCDD和这些抑制剂共同处理细胞，显着降低了核雌激素受体复合物的水平。TCDD和几个同系物的结构-活性关系是相似的，既占用核雌激素受体水平的减少和几个芳烃（Ah）受体激动剂的活动，这些结果支持的Ah受体在这些过程中的作用。
Treatment of MCF-7 human breast cancer cells with 17 beta-[3H]estradiol resulted in a rapid accumulation of occupied nuclear estrogen receptor complex in which levels were maximized within 1 h and decreased after 3 h. Pretreatment of the cells with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) 6 or 12 h prior to the addition of the radiolabeled hormone resulted in a 38 and 63% reduction in the levels of the occupied nuclear estrogen receptor, respectively, whereas addition of TCDD 1 h prior to the radioligand did not cause any significant change in the levels of the occupied nuclear receptor using velocity sedimentation analysis. Moreover, it was also shown with estrogen receptor antibodies that the TCDD-mediated dose-dependent decrease in occupied nuclear receptor levels was paralleled by a comparable decrease in immunoreactive protein at concentrations of 10(-8) to 10(-11) M TCDD. The reduction in levels of the occupied nuclear estrogen receptor was not due to increased estradiol metabolism since a significant reduction was observed at TCDD concentrations (10(-11) to 10(-13) M) which do not induce cytochrome P-450-dependent monooxygenase enzyme activities in MCF-7 cells. Treatment of the MCF-7 cells with actinomycin D or cycloheximide resulted in a greater than 2-fold increase in levels of the occupied nuclear estrogen receptor, and cotreatment of the cells with both TCDD and these inhibitors significantly decreased levels of the nuclear estrogen receptor complex. The structure-activity relationships for TCDD and several congeners were similar for both the reduction of occupied nuclear estrogen receptor levels and several aryl hydrocarbon (Ah) receptor agonist activities, and these results support a role of the Ah receptor in these processes.