Aryl hydrocarbon receptor-mediated antiestrogenic and antitumorigenic activity of diindolylmethane
Aryl hydrocarbon receptor-mediated antiestrogenic and antitumorigenic activity of diindolylmethane
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DOI：
10.1093/carcin/19.9.1631
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发表时间：
1998-09-01
期刊：
影响因子：
4.7
通讯作者：
Safe, S
中科院分区：
文献类型：
--
作者：
Chen, I;McDougal, A;Safe, S
植物化学物质如吲哚-3-甲醇（I3 C）和萝卜硫素是十字花科蔬菜的组分，其表现出与改变的致癌物代谢和解毒相关的抗肿瘤活性，二吲哚基甲烷（DIM）是肠道中形成的I3 C的主要酸催化代谢产物，其与芳烃受体（AhR）结合，用10-二吲哚基甲烷治疗MCF-7人乳腺癌细胞，50 μ M DIM导致细胞核AhR复合物的快速形成，并在浓度>50 μ M时观察到CYP 1A 1基因表达的诱导。先前的研究表明，2，3，7，8-四氯二苯并-p-二恶英（TCDD），一种高亲和力AhR配体，抑制MCF-7细胞中17 β-雌二醇（E2）诱导的反应和雌性Sprague-Dawley大鼠中E2依赖性7，12-二甲基苯并蒽（DMBA）诱导的乳腺肿瘤的生长。本研究结果表明，与TCDD一样，DIM抑制E2诱导的MCF-7细胞增殖，在瞬时转染E2应答质粒的细胞中抑制报告基因活性（含有蛙卵黄蛋白原A2基因启动子插入片段）并下调核雌激素受体，此外，昏暗（5 mg/kg，每隔一天）也抑制DMBA诱导的Sprague-Dawley大鼠乳腺肿瘤生长，并且这不伴有肝CYP 1A 1依赖性活性的诱导，因此，DLM代表了一类新的相对无毒的基于AhR的抗雌激素，其抑制啮齿动物中的Ea依赖性肿瘤生长，并且目前的研究集中于开发用于临床治疗乳腺癌的类似物。
Phytochemicals such as indole-3-carbinol (I3C) and sulforaphane are components of cruciferous vegetables which exhibit antitumorigenic activity associated with altered carcinogen metabolism and detoxification, Diindolyl-methane (DIM) is a major acid-catalyzed metabolite of I3C formed in the gut that binds to the aryl hydrocarbon receptor (AhR) and treatment of MCF-7 human breast cancer cells with 10-50 mu M DIM resulted in rapid formation of the nuclear AhR complex and induction of CYP1A1 gene expression was observed at concentrations >50 mu M, Previous studies have demonstrated that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a high affinity AhR ligand, inhibits 17 beta-estradiol (E2)-induced responses in MCF-7 cells and growth of E2-dependent 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumors in female Sprague-Dawley rats. Results of this study show that like TCDD, DIM inhibits E2-induced proliferation of MCF-7 cells, reporter gene activity in cells transiently transfected with an E2-responsive plasmid (containing a frog vitellogenin A2 gene promoter insert) and down-regulates the nuclear estrogen receptor, Moreover, DIM (5 mg/kg every other day) also inhibits DMBA-induced mammary tumor growth in Sprague-Dawley rats and this was not accompanied by induction of hepatic CYP1A1-dependent activity, Thus, DLM represents a new class of relatively non-toxic AhR-based antiestrogens that inhibit Ea-dependent tumor growth in rodents and current studies are focused on development of analogs for clinical treatment of breast cancer.