Bioavailability and activity of dietary naringenin as a chemopreventive agent

描述(由申请人提供)：2型糖尿病增加了绝经后妇女患乳腺癌的风险。流行病学研究最近显示，降糖药物二甲双胍可以减少糖尿病女性的乳腺癌。我们最近报道了类黄烷素，柚皮苷元类似二甲双胍的作用，以降低肝细胞葡萄糖的产生。在几种癌症的临床前模型中，柚皮苷作为一种化学预防药物出现。由于目前关于饮食柚皮素在乳腺中的生物利用度、组织蓄积量和生物活性的研究尚未见报道，因此，我们建议定量研究柚皮苷元在乳腺组织和血液中的蓄积量，以确定饮食柚皮苷元对肥胖雌性小鼠乳腺肿瘤生长的调节能力。本研究的目的有三个。在目标1中，我们将检验这样一种假设，即增加饮食中的柚皮苷元剂量会导致剂量- 在血液和组织中迅速积累柚皮素，对食物摄入量和体重增加没有不利影响。在目标2中，我们将检验柚皮苷元降低肿瘤生长速度的假设。在目标3中，我们将检验这一假说，即饮食中的柚皮苷元调节与肿瘤发生和代谢有关的信号事件。这项提案中概述的实验的完成将决定未来是否有理由进行实验，以确定饮食中的柚皮苷是一种预防乳腺癌的药物。

DESCRIPTION (provided by applicant): Type 2 diabetes increases the risk for developing breast cancer in postmenopausal women. Epidemiological studies have recently revealed that the glucose-lowering drug, metformin, reduces breast cancer in women with diabetes. We recently reported that the flavanoid, naringenin acts like metformin to lower glucose production by hepatocytes. Naringenin is surfacing as a chemopreventive agent in several preclinical models for cancer. Since the bioavailability, tissue accumulation and biological activity of dietar naringenin in mammary gland have not been reported, we propose to quantify the accumulation of naringenin in mammary tissues and blood then determine the ability of dietary naringenin to modulate growth of mammary tumors in obese female mice. There are three aims of this study. In Aim 1, we will test the hypothesis that increasing doses of dietary naringenin result in a dose- responsive accumulation of naringenin in blood and tissues without detrimental effects on food intake and weight gain. In Aim 2, we will test the hypothesis that naringenin reduces the rate of growth of tumors. In Aim 3, we will test the hypothesis that dietary naringenin modulates signaling events involved with tumorigenesis and metabolism. Accomplishment of the experiments outlined in this proposal will determine whether there is rationale for future experiments to identify dietary naringenin as a preventive agent against breast cancer.