Dietary Isothiocyanates in Cancer Prevention: Effects of Estrogen Metabolism

描述(申请人提供)：预防乳腺癌是一项非常重要的工作。异硫氰酸酯(ITCs)是一种主要存在于饮食中的十字花科蔬菜中的饮食成分，研究了它们的化学预防特性，特别是在啮齿动物模型中对致癌物诱导的肿瘤形成的预防作用。此外，ITCs是许多草本补充剂的成分，包括每日十字花科植物补充剂、西兰花芽和BioBasics等。食用十字花科蔬菜与患肺癌、结肠癌、胃癌和前列腺癌的风险成反比，据报道，绝经后女性患乳腺癌的风险最高可降低20%-40%。我们的初步数据表明，暴露于苯乙基ITC或萝卜硫醚可降低人乳腺癌MCF-7细胞中17β-雌二醇的浓度，而口服苯乙基ITC可降低大鼠肝脏雌二醇的浓度。我们的假设是，饮食中的ITCs是乳腺癌的有效防御剂，其预防乳腺癌的作用机制之一是它们改变了血浆和组织(包括乳腺组织)中17β-雌二醇的浓度。在本应用程序中，我们将检查主要的膳食ITCs之一，苯乙基ITC(PEITC)。本应用的具体目的是：(1)确定PEITC对大鼠肝脏和乳腺组织中雌二醇和雌二醇结合物以及对硫酸盐和葡萄糖醛酸化物结合物活性的浓度和时间依赖效应。我们的假设是，低浓度的PEITC会降低雌二醇浓度，其机制主要是由于诱导第二相(共轭)代谢。(2)在雌激素依赖的动物乳腺癌模型N-甲基-N-亚硝脲(NMU)诱导的大鼠乳腺癌模型中，确定PEITC对(A)肿瘤的发生频率、大小和潜伏期以及(B)雌激素和雌激素代谢产物浓度的剂量依赖性影响。一些大鼠将接受17β-雌二醇治疗，以逆转PEITC对雌激素代谢的影响。这项拟议的研究将提供有关ITC对雌二醇代谢的影响的初步信息，作为ITCs预防乳腺癌作用的一个潜在机制：这一机制以前还没有被研究过。由于饮食化合物不被视为“药物”，也与毒性无关，因此饮食中使用异硫氰酸酯代表了一种可能被健康人广泛接受的化学预防方法。

DESCRIPTION (provided by applicant): There is a crucial need for breast cancer prevention. Isothiocyanates (ITCs) are dietary constituents present predominantly in cruciferous vegetables present in the diet, and investigated for their chemopreventive properties, particularly against carcinogen-induced tumorigenesis in rodent models. Additionally, ITCs are constituents of numerous herbal supplements including Daily Cruciferous Plus, Broccoli Sprouts, and BioBasics, among others. Consumption of cruciferous vegetables is inversely associated with the risk of cancer of the lung, colon, stomach and prostate, and has been reported to lower the risk of breast cancer by as much as 20-40% in post-menopausal women. Our preliminary data indicates that exposure to phenethyl ITC or sulforaphane lowers 17beta-estradiol concentrations in human breast cancer MCF-7 cells and oral phenethyl ITC administration to rats produces decreased liver estradiol concentrations. Our hypothesis is that dietary ITCs represent effective preventive agents in breast cancer, and one mechanism of action contributing to their breast cancer preventive effect is their alteration of 17beta-estradiol concentrations in plasma and tissues, including mammary tissue. In this application we will examine one of the major dietary ITCs, phenethyl ITC (PEITC). The specific aims of this application are: (1) To determine the concentration- and time-dependent effects of PEITC on estradiol and estradiol conjugates in rat liver and mammary tissue, and on sulfate and glucuronide conjugation activities. Our hypothesis is that PEITC at low concentrations will decrease estradiol concentrations, with the mechanism predominantly due to induction of Phase II (conjugative) metabolism. (2) To determine the dose-dependent effects of PEITC on (a) the tumor frequency, size and latency and (b) estrogen and estrogen metabolite concentrations in an estrogen-dependent animal breast cancer model, N-methyl-N-nitrosourea (NMU)-induced carcinogenesis in rats. Some rats will be treated with17beta-estradiol to reverse the effects of PEITC on estrogen metabolism. The proposed studies will provide preliminary information on ITC-mediated effects on estradiol metabolism, as one potential mechanism underlying the breast cancer preventive effects of ITCs: this mechanism has not previously been investigated for ITCs. Since dietary compounds are not perceived as "drugs", and are not associated with toxicity, the use of dietary isothiocyanates represents an approach for chemoprevention that may be widely- acceptable by healthy individuals.