van Meeuwen J A, Korthagen N, de Jong P C, Piersma A H, van den Berg M
Institute for Risk Assessment Sciences (IRAS), Utrecht University, PO Box 80177, 3508 TD Utrecht, The Netherlands.
Toxicol Appl Pharmacol. 2007 Jun 15;221(3):372-83. doi: 10.1016/j.taap.2007.03.016. Epub 2007 Mar 27.
In the public opinion, phytochemicals (PCs) present in the human diet are often considered beneficial (e.g. by preventing breast cancer). Two possible mechanisms that could modulate tumor growth are via interaction with the estrogen receptor (ER) and inhibition of aromatase (CYP19). Multiple in vitro studies confirmed that these compounds act estrogenic, thus potentially induce tumor growth, as well as aromatase inhibitory, thus potentially reduce tumor growth. It is thought that in the in vivo situation breast epithelial (tumor) cells communicate with surrounding connective tissue by means of cytokines, prostaglandins and estradiol forming a complex feedback mechanism. Recently our laboratory developed an in vitro co-culture model of healthy mammary fibroblasts and MCF-7 cells that (at least partly) simulated this feedback mechanism (M. Heneweer et al., TAAP vol. 202(1): 50-58, 2005). In the present study biochanin A, chrysin, naringenin, apigenin, genistein and quercetin were studied for their estrogenic properties (cell proliferation, pS2 mRNA) and aromatase inhibition in MCF-7 breast tumor cells, healthy mammary fibroblasts and their co-culture. The proliferative potency of these compounds in the MCF-7 cells derived from their EC(50)s decreased in the following order: estadiol (4*10(-3) nM)>biochanin A (9 nM)>genistein (32 nM)>testosterone (46 nM)>naringenin (287 nM)>apigenin (440 nM)>chrysin (4 microM). The potency to inhibit aromatase derived from their IC(50)s decreased in the following order: chrysin (1.5 microM)>naringenin (2.2 microM)>genistein (3.6 microM)>apigenin (4.1 microM)>biochanin A (25 microM)>quercetin (30 microM). The results of these studies show that these PCs can induce cell proliferation or inhibit aromatase in the same concentration range (1-10 microM). Results from co-cultures did not elucidate the dominant effect of these compounds. MCF-7 cell proliferation occurs at concentrations that are not uncommon in blood of individuals using food supplements. Results also indicate that estrogenicity of these PCs is quantitatively more sensitive than aromatase inhibition. It is suggested that perhaps a more cautionary approach should be taken for these PCs before taken as food supplements.
在公众认知中，人类饮食中存在的植物化学物质（PCs）通常被认为是有益的（例如预防乳腺癌）。可能调节肿瘤生长的两种机制是通过与雌激素受体（ER）相互作用以及抑制芳香化酶（CYP19）。多项体外研究证实，这些化合物具有雌激素样作用，因此可能诱导肿瘤生长，同时也具有芳香化酶抑制作用，因此可能减少肿瘤生长。据认为，在体内情况下，乳腺上皮（肿瘤）细胞通过细胞因子、前列腺素和雌二醇与周围结缔组织进行通讯，形成复杂的反馈机制。最近，我们实验室开发了一种健康乳腺成纤维细胞和MCF-7细胞的体外共培养模型，该模型（至少部分地）模拟了这种反馈机制（M. Heneweer等人，《毒理学应用与药物代谢》第202卷第1期：50 - 58页，2005年）。在本研究中，对生物chanin A、白杨素、柚皮素、芹菜素、染料木黄酮和槲皮素在MCF-7乳腺肿瘤细胞、健康乳腺成纤维细胞及其共培养物中的雌激素特性（细胞增殖、pS2 mRNA）和芳香化酶抑制作用进行了研究。这些化合物在MCF-7细胞中的增殖效力从其半数有效浓度（EC50）来看，按以下顺序降低：雌二醇（4×10⁻³ nM）＞生物chanin A（9 nM）＞染料木黄酮（32 nM）＞睾酮（46 nM）＞柚皮素（287 nM）＞芹菜素（440 nM）＞白杨素（4 μM）。抑制芳香化酶的效力从其半数抑制浓度（IC50）来看，按以下顺序降低：白杨素（1.5 μM）＞柚皮素（2.2 μM）＞染料木黄酮（3.6 μM）＞芹菜素（4.1 μM）＞生物chanin A（25 μM）＞槲皮素（30 μM）。这些研究结果表明，这些植物化学物质在相同浓度范围（1 - 10 μM）内可以诱导细胞增殖或抑制芳香化酶。共培养的结果并未阐明这些化合物的主要作用。在使用食品补充剂的个体血液中，MCF-7细胞增殖发生的浓度并不罕见。结果还表明，这些植物化学物质的雌激素活性在定量上比芳香化酶抑制作用更敏感。建议在将这些植物化学物质用作食品补充剂之前，或许应采取更谨慎的方法。
