Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood Street, Chicago, IL 60612-7231, USA.
Cancer Prev Res (Phila). 2012 Jan;5(1):73-81. doi: 10.1158/1940-6207.CAPR-11-0348. Epub 2011 Oct 13.
Long-term exposure to estrogens including those in traditional hormone replacement therapy (HRT) increases the risk of developing hormone-dependent cancers. As a result, women are turning to over-the-counter (OTC) botanical dietary supplements, such as black cohosh (Cimicifuga racemosa) and hops (Humulus lupulus), as natural alternatives to HRT. The two major mechanisms which likely contribute to estrogen and/or HRT cancer risk are: the estrogen receptor-mediated hormonal pathway; and the chemical carcinogenesis pathway involving formation of estrogen quinones that damage DNA and proteins, hence initiating and promoting carcinogenesis. Because, OTC botanical HRT alternatives are in widespread use, they may have the potential for chemopreventive effects on estrogen carcinogenic pathways in vivo. Therefore, the effect of OTC botanicals on estrogen-induced malignant transformation of MCF-10A cells was studied. Cytochrome P450 catalyzed hydroxylation of estradiol at the 4-position leads to an o-quinone believed to act as the proximal carcinogen. Liquid chromatography/tandem mass spectrometry analysis of estradiol metabolites showed that 4-hydroxylation was inhibited by hops, whereas black cohosh was without effect. Estrogen-induced expression of CYP450 1B1 and CYP450 1A1 was attenuated by the hops extract. Two phenolic constituents of hops (xanthohumol, XH; 8-prenylnaringenin, 8-PN) were tested: 8-PN was a potent inhibitor, whereas XH had no effect. Finally, estrogen-induced malignant transformation of MCF-10A cells was observed to be significantly inhibited by hops (5 μg/mL) and 8-PN (50 nmol/L). These data suggest that hops extracts possess cancer chemopreventive activity through attenuation of estrogen metabolism mediated by 8-PN.
长期暴露于雌激素，包括传统激素替代疗法（HRT）中的雌激素，会增加患激素依赖性癌症的风险。因此，女性正在转向非处方（OTC）植物性膳食补充剂，如黑升麻（Cimicifuga racemosa）和啤酒花（Humulus lupulus），作为 HRT 的天然替代品。可能导致雌激素和/或 HRT 癌症风险的两个主要机制是：雌激素受体介导的激素途径；以及涉及形成雌激素醌的化学致癌途径，这些醌会损害 DNA 和蛋白质，从而引发和促进致癌作用。由于 OTC 植物性 HRT 替代品的广泛使用，它们可能具有对体内雌激素致癌途径的化学预防作用。因此，研究了 OTC 植物对 MCF-10A 细胞中雌激素诱导的恶性转化的影响。细胞色素 P450 在 4 位催化雌二醇的羟化作用，生成被认为是近位致癌物的 o-醌。雌二醇代谢物的液相色谱/串联质谱分析表明，啤酒花抑制了 4-羟化作用，而黑升麻则没有作用。啤酒花提取物减弱了雌激素诱导的 CYP450 1B1 和 CYP450 1A1 的表达。对啤酒花中的两种酚类成分（黄腐酚，XH；8-异戊烯基柚皮素，8-PN）进行了测试：8-PN 是一种有效的抑制剂，而 XH 则没有作用。最后，观察到啤酒花（5μg/mL）和 8-PN（50nmol/L）显著抑制了 MCF-10A 细胞的雌激素诱导恶性转化。这些数据表明，啤酒花提取物通过 8-PN 减弱雌激素代谢介导的作用，具有癌症化学预防活性。
