Makela S, Davis VL, Tally WC, Korkman J, Salo L, Vihko R, Santti R, Korach KS
Institute of Biomedicine, University of Turku, SF-20520 Turku, Finland.
Environ Health Perspect. 1994 Jun;102(6-7):572-8. doi: 10.1289/ehp.94102572.
Dietary estrogens are believed to exert their estrogenic or antiestrogenic (chemopreventive) action in estrogen responsive cells by interacting with the estrogen receptor (ER). The present study was undertaken to evaluate a direct role of ER in estrogenic or antiestrogenic activities of three dietary estrogens (coumestrol, genistein and zearalenone). HeLa cells were transiently co-transfected with an expression vector for ER and an estrogen-responsive reporter gene construct. Coumestrol, genistein, and zearalenone all increased the activity of the reporter gene, only in the presence of the ER, and the activation was blocked with the ER antagonist ICI 164,384, demonstrating an ER-specific, agonist response. In addition, in MCF-7 cells, coumestrol and zearalenone increased the expression of the estrogen-responsive pS2 gene. Coumestrol and genistein inhibited the purified estrogen-specific 17ß-hydroxysteroid oxidoreductase enzyme and the conversion of estrone to 17ß-estradiol in T-47D cells, which contain this enzyme. However, they did not inhibit the estrone-induced proliferation of T-47D cells. In conclusion, coumestrol, genistein, and zearalenone are all potent estrogens in vitro, and they act through ER mediated mechanism. Our findings give no evidence to support the idea that these compounds act as antiestrogens through competition for the binding sites of ER or by inhibition of the conversion of estrone to 17ß-estradiol in breast cancer cells, since this effect was nullified by their agonist action on cell proliferation. Therefore, their suggested chemopreventive action in estrogen-related cancers must be mediated through other mechanisms.
膳食雌激素被认为通过与雌激素受体(ER)相互作用,在雌激素反应性细胞中发挥其雌激素或抗雌激素(化学预防)作用。本研究旨在评估ER在三种膳食雌激素(香豆雌酚、染料木黄酮和玉米赤霉烯酮)的雌激素或抗雌激素活性中的直接作用。HeLa细胞用ER表达载体和雌激素反应性报告基因构建体进行瞬时共转染。香豆雌酚、染料木黄酮和玉米赤霉烯酮均仅在存在ER的情况下增加报告基因的活性,并且这种激活被ER拮抗剂ICI 164,384阻断,表明存在ER特异性的激动剂反应。此外,在MCF-7细胞中,香豆雌酚和玉米赤霉烯酮增加了雌激素反应性pS2基因的表达。香豆雌酚和染料木黄酮抑制了纯化的雌激素特异性17β-羟基类固醇氧化还原酶以及含有该酶的T-47D细胞中雌酮向17β-雌二醇的转化。然而,它们并未抑制雌酮诱导的T-47D细胞增殖。总之,香豆雌酚、染料木黄酮和玉米赤霉烯酮在体外均为强效雌激素,且它们通过ER介导的机制发挥作用。我们的研究结果没有证据支持这些化合物通过竞争ER结合位点或抑制乳腺癌细胞中雌酮向17β-雌二醇的转化而作为抗雌激素发挥作用的观点,因为这种作用因其对细胞增殖的激动剂作用而无效。因此,它们在雌激素相关癌症中所提出的化学预防作用必须通过其他机制介导。