Bioavailability and activity of dietary naringenin as a chemopreventive agent

描述（由申请人提供）：2型糖尿病增加绝经后妇女患乳腺癌的风险。最近的流行病学研究表明，降糖药物二甲双胍可以减少糖尿病妇女患乳腺癌的几率。我们最近报道，类黄烷，柚皮素的作用像二甲双胍，以降低肝细胞的葡萄糖生产。柚皮素作为一种化学预防剂出现在几种癌症的临床前模型中。由于膳食柚皮素在乳腺中的生物利用度、组织蓄积和生物活性尚未报道，我们建议量化柚皮素在乳腺组织和血液中的蓄积，然后确定膳食柚皮素调节肥胖雌性小鼠乳腺肿瘤生长的能力。本研究有三个目的。在目标1中，我们将检验这样的假设，即增加剂量的膳食柚皮素导致剂量- 柚皮素在血液和组织中的反应性积累，对食物摄入和体重增加没有有害影响。在目标2中，我们将检验柚皮素降低肿瘤生长速率的假设。在目标3中，我们将检验膳食柚皮素调节与肿瘤发生和代谢有关的信号事件的假设。本提案中概述的实验的完成将决定未来实验是否有理由确定膳食柚皮素作为乳腺癌预防剂。

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.