Zhang Shu, Qin Chunhua, Safe Stephen H
Department of Veterinary Physiology and Pharmacology, Texas AM University, College Station 77843-4466, USA.
Environ Health Perspect. 2003 Dec;111(16):1877-82. doi: 10.1289/ehp.6322.
Chemoprotective phytochemicals exhibit multiple activities and interact with several cellular receptors, including the aryl hydrocarbon (Ah) receptor (AhR). In this study we investigated the AhR agonist/antagonist activities of the following flavonoids: chrysin, phloretin, kaempferol, galangin, naringenin, genistein, quercetin, myricetin, luteolin, baicalein, daidzein, apigenin, and diosmin. We also investigated the AhR-dependent activities of cantharidin and emodin (in herbal extracts) in Ah-responsive MCF-7 human breast cells, HepG2 human liver cancer cells, and mouse Hepa-1 cells transiently or stably transfected with plasmids expressing a luciferase reporter gene linked to multiple copies of a consensus dioxin-responsive element. The AhR agonist activities of the compounds (1 and 10 micro M) were as high as 25% of the maximal response induced by 5 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and their potencies were dependent on cell context. Galangin, genistein, daidzein, and diosmin were active only in Hepa-1 cells, and cantharidin induced activity only in human HepG2 and MCF-7 cells. Western blot analysis confirmed that baicalein and emodin also induced CYP1A1 protein in the human cancer cell lines. The AhR antagonist activities of four compounds inactive as agonists in MCF-7 and HepG2 cells (kaempferol, quercetin, myricetin, and luteolin) were also investigated. Luteolin was an AhR antagonist in both cell lines, and the inhibitory effects of the other compound were dependent on cell context. These data suggest that dietary phytochemicals exhibit substantial cell context-dependent AhR agonist as well as antagonist activities. Moreover, because phytochemicals and other AhR-active compounds in food are present in the diet at relatively high concentrations, risk assessment of dietary toxic equivalents of TCDD and related compounds should also take into account AhR agonist/antagonist activities of phytochemicals.
具有化学保护作用的植物化学物质具有多种活性，并与多种细胞受体相互作用，包括芳烃（Ah）受体（AhR）。在本研究中，我们调查了以下黄酮类化合物的AhR激动剂/拮抗剂活性：白杨素、根皮素、山奈酚、高良姜素、柚皮素、染料木黄酮、槲皮素、杨梅素、木犀草素、黄芩素、大豆苷元、芹菜素和地奥司明。我们还研究了斑蝥素和大黄素（在草药提取物中）在Ah反应性MCF-7人乳腺癌细胞、HepG2人肝癌细胞以及瞬时或稳定转染了表达与多个拷贝的共有二噁英反应元件连接的荧光素酶报告基因的质粒的小鼠Hepa-1细胞中的AhR依赖性活性。这些化合物（1和10微摩尔）的AhR激动剂活性高达5 nM 2,3,7,8-四氯二苯并-p-二噁英（TCDD）诱导的最大反应的25%，其效力取决于细胞环境。高良姜素、染料木黄酮、大豆苷元和地奥司明仅在Hepa-1细胞中有活性，而斑蝥素仅在人HepG2和MCF-7细胞中诱导活性。蛋白质印迹分析证实，黄芩素和大黄素也在人癌细胞系中诱导CYP1A1蛋白。我们还研究了在MCF-7和HepG2细胞中作为激动剂无活性的四种化合物（山奈酚、槲皮素、杨梅素和木犀草素）的AhR拮抗剂活性。木犀草素在这两种细胞系中都是AhR拮抗剂，其他化合物的抑制作用取决于细胞环境。这些数据表明，膳食植物化学物质表现出显著的细胞环境依赖性AhR激动剂以及拮抗剂活性。此外，由于食物中的植物化学物质和其他具有AhR活性的化合物在饮食中以相对较高的浓度存在，对TCDD和相关化合物的膳食毒性当量进行风险评估时也应考虑植物化学物质的AhR激动剂/拮抗剂活性。
