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。流行病学研究最近表明，降糖药物二甲双胍可以降低糖尿病女性的乳腺癌发病率。我们最近报道了类黄酮，柚皮素像二甲双胍一样降低肝细胞的葡萄糖产量。柚皮素作为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，我们建议定量研究柚皮素在乳腺组织和血液中的蓄积，从而确定膳食柚皮素对肥胖雌性小鼠乳腺肿瘤生长的调节能力。这项研究有三个目的。在目标1中，我们将检验假设，增加膳食柚皮素的剂量会导致剂量-

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. PUBLIC HEALTH RELEVANCE: Type 2 diabetes increases the risk for developing breast cancer in postmenopausal women. Our goal is to find dietary approaches that complement weight loss to reduce the risk and mortality from breast cancer in postmenopausal women. Experiments outlined in this application seek to use a pre-clinical model for dysregulated metabolism to quantify the accumulation and chemopreventive activity of naringenin in mammary tumorigenesis.