6-Methyl-1,3,8-trichlorodibenzofuran (MCDF) as an antiestrogen in human and rodent cancer cell lines: evidence for the role of the Ah receptor.
6-Methyl-1,3,8-trichlorodibenzofuran (MCDF) as an antiestrogen in human and rodent cancer cell lines: evidence for the role of the Ah receptor.
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DOI：
10.1016/0041-008x(92)90130-k
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发表时间：
1992-04
影响因子：
3.8
通讯作者：
T. Zachrewski;M. Harris;L. Biegel;V. Morrison;Mark Merchant;S. Safe
中科院分区：
文献类型：
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作者：
T. Zachrewski;M. Harris;L. Biegel;V. Morrison;Mark Merchant;S. Safe
6-甲基-1，3，8-三氯二苯并呋喃（6-Methyl-1，3，8-trichlorodibenzofuran，MCDF）是2，3，7，8-四氯二苯并二恶英的一种无毒类似物。用100 nm MCDF处理芳烃（Ah）敏感性MCF-7人乳腺癌细胞，可抑制17β-雌二醇诱导的增殖和34、52和160 kDa蛋白的分泌。用17β-[3 H]雌二醇处理细胞后，100 nm MCDF导致这些细胞中放射性标记的核雌激素受体（ER）复合物的蓄积减少。在平行实验中，MCDF的抗雌激素作用也确定在AH-响应野生型Hepa 1c 1c 7细胞和AH-非响应类1和类2突变细胞。用17β-[3 H]雌二醇和100 nm MCDF处理野生型细胞，导致这些细胞中放射性标记的细胞核ER复合物的蓄积减少，而通过速度沉降分析确定，在突变型细胞中未观察到显著影响。使用ER抗体测量免疫反应性细胞核ER的减少获得了相当的结果。此外，放线菌素D和放线菌酮抑制MCDF介导的Hepa 1c 1c 7野生型细胞核ER水平的降低。尽管100 nm MCDF在MCF-7或Hepa 1c 1c 7细胞系中不诱导细胞色素P-450依赖性单加氧酶，但用100 nm MCDF处理的MCF-7细胞的核提取物与合成的共有二恶英响应元件（26个碱基的寡核苷酸双链体）孵育，在凝胶阻滞试验中产生阻滞条带。这些数据表明，MCDF的抗雌激素作用不需要诱导CYP 1A 1基因表达，但可能涉及其他基因的诱导。
6-Methyl-1,3,8-trichlorodibenzofuran (MCDF) is a relatively nontoxic analog of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Treatment of aryl hydrocarbon (Ah)-responsive MCF-7 human breast cancer cells with 100 nm MCDF resulted in the inhibition of 17β-estradiol-induced proliferation and the secretion of the 34-, 52-, and 160-kDa proteins. After treatment of the cells with 17β-[3H]estradiol, 100 nm of MCDF caused a decrease in the accumulation of the radiolabeled nuclear estrogen receptor (ER) complex in these cells. In parallel experiments, the antiestrogenic effects of MCDF were also determined in Ah-responsive wild-type Hepa 1c1c7 cells and Ah-nonresponsive class 1 and class 2 mutant cells. Treatment of the wild-type cells with 17β-[3H]estradiol and 100 nm MCDF caused a decrease in the accumulation of radiolabeled nuclear ER complex in these cells whereas no significant effects were observed in the mutant cells as determined by velocity sedimentation analysis. Comparable results were obtained using ER antibodies to measure the decrease in immunoreactive nuclear ER. In addition, both actinomycin D and cycloheximide inhibited the MCDF-mediated decrease of nuclear ER levels in the Hepa 1c1c7 wild-type cells. Although 100 nm MCDF did not induce cytochrome P-450-dependent monooxygenases in the MCF-7 or Hepa 1c1c7 cell lines, incubation of nuclear extracts from the MCF-7 cells treated with 100 nm MCDF with a synthetic consensus dioxin responsive element (an oligonucleotide duplex of 26 bases) gave a retarded band in a gel-retardation assay. The data suggest that the antiestrogenic effects of MCDF does not require the induction of the CYP1A1 gene expression but may involve the induction of other genes.