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

• Applicant: Professor Dr. Manfred Metzler
• Subject Area: Cell Biology
• Term: from 2006 to 2008
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 23591201

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.

• DFG Programme: Research Grants