Dietary Isothiocyanates in Cancer Prevention: Effects of Estrogen Metabolism

描述（由申请人提供）：我们急需预防乳腺癌。异硫氰酸酯（ITCs）主要存在于饮食中的十字花科蔬菜中，并被研究其化学预防特性，特别是在啮齿动物模型中对致癌物诱导的肿瘤发生。此外，ITCs是许多草药补充剂的成分，包括每日十字花科、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呈负相关，据报道，食用十字花科蔬菜可将绝经后妇女患乳腺癌的风险降低20-40%。我们的初步数据表明，暴露于苯乙基ITC或萝卜硫素可降低人乳腺癌MCF-7细胞中的17 - β -雌二醇浓度，大鼠口服苯乙基ITC可降低肝脏雌二醇浓度。我们的假设是，饮食中的ITCs是乳腺癌的有效预防剂，其预防乳腺癌的作用机制之一是改变血浆和组织（包括乳腺组织）中的17 - β -雌二醇浓度。在本应用中，我们将研究一种主要的膳食ITC，苯乙酯ITC （PEITC）。本应用程序的具体目的是：(1)确定PEITC对大鼠肝脏和乳腺组织中雌二醇和雌二醇偶联物的浓度和时间依赖性影响，以及对硫酸盐和葡萄糖醛酸盐偶联活性的影响。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II期（共轭）代谢。(2)在雌激素依赖动物乳腺癌模型n-甲基-n -亚硝基脲（NMU）诱导的大鼠癌变中，确定PEITC对(a)肿瘤发生频率、大小、潜伏期和(b)雌激素及雌激素代谢物浓度的剂量依赖性影响。一些大鼠将接受17 -雌二醇治疗，以逆转PEITC对雌激素代谢的影响。拟议的研究将提供关于ITCs介导的雌二醇代谢作用的初步信息，作为ITCs预防乳腺癌作用的一种潜在机制：这一机制此前尚未对ITCs进行研究。由于膳食化合物不被视为“药物”，也与毒性无关，因此使用膳食异硫氰酸酯是一种可能被健康个体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.