Stimulation of the Glucuronidation of Estradiol by Phytochemicals: A Protective Mechanism for Hormonal Carcinogenesis?

对于乳腺癌和子宫内膜癌，长期暴露于高组织水平的内源性雌激素17 β-雌二醇（E2）被认为是一个重要的风险因素。大豆异黄酮被认为可以预防E2介导的癌症，但其保护机制尚不清楚。在过去的研究项目中，我们已经观察到，大豆黄豆苷元激活，在无细胞条件下，尿苷二磷酸葡萄糖醛酸转移酶（UGT）催化的葡萄糖醛酸化的E2，这可能会导致增强清除和降低组织水平的E2在体内。在本项目中，我们建议（1）研究其他具有假定的癌症保护潜力的植物化学物质是否也会影响E2的葡萄糖醛酸化，（2）研究在无细胞条件下观察到的大豆黄酮对E2葡萄糖醛酸化的刺激作用是否也在完整细胞和E2致癌性的靶组织中起作用，（3）研究植物生长调节因子对E2及其I相代谢产物UGT 1A 1和UGT 2B 7基因调控的影响。这项研究的长期目标是了解膳食植物化学物质的癌症保护作用的机制，这可能最终导致饮食降低激素癌症的发病率。

For cancer of the breast and endometrium, prolonged exposure to high tissue levels of the endogenous estrogen 17 β-estradiol (E2) is considered a significant risk factor. Soy isoflavones are believed to protect against E2-mediated cancer, but the mechanisms of protection are as yet unknown. In the past research project, we have observed that the soy isoflavone daidzein activates, under cell-free conditions, the uridine diphosphoglucuronosyltransferase (UGT) catalyzing the glucuronidation of E2, which might lead to enhanced clearance and lower tissue levels of E2 in vivo. In the present project, we propose (1) to investigate whether other phytochemicals with putative cancer-protective potential will also affect the glucuronidation of E2, (2) to study whether the stimulatory effect of daidzein on E2 glucuronidation observed under cell-free conditions is also operative in intact cells and in target tissues of E2 carcinogenicity, and (3) to study the effect of isoflavones and other protective phytochemicals on the gene regulation of UGT1A1 and UGT2B7, which are crucial for the clearance of E2 and its phase I metabolites. The long-term goal of this research is to understand the mechanism of the cancer-protective effects of dietary phytochemicals, which may eventually lead to a diet lowering the incidence of hormonal cancer.