Cruciferous vegetable feeding and inflammation: effect of GST genotypes

描述（由申请人提供）：食用十字花科（即花椰菜科）蔬菜与几种癌症的风险较低相关，并且部分依赖于GSTM1/GSTT1基因型。异硫氰酸酯（ITC）是从十字花科植物中的硫代葡萄糖苷中提取的生物活性成分，通过激活转录因子Nrf-2来调节对致癌物和性类固醇解毒的酶。证据还支持ITC在另一个对癌变至关重要的信号通路中发挥作用，即抑制核因子κ b （NF-kB）。NF-kB是参与炎症过程的基因，如细胞因子、趋化因子、粘附分子等参与免疫反应的可溶性因子的转录因子和中枢介质。ITC抑制nf - kb介导的过程，因此可能减少炎症——一个公认的致癌风险因素。许多细胞因子水平较高与癌症风险增加有关。ITC代谢的变化可能影响ITC暴露和对这些药物的生物反应。谷胱甘肽s -转移酶（GST）M1和GSTT1代谢ITC，生物反应和ITC药代动力学的基因型差异已被报道。然而，尚不清楚这些变异是否影响ITC代谢或其他未知机制。关于GSTM1/GSTT1基因型对十字花科蔬菜的修饰作用已有较完善的文献；然而，其他GST异构体的数据较弱。有证据表明，转录因子Nrf-2的激活，如在ITC中发生的，可能会减少通过持续的NF-kB信号传导建立的促炎周期。我们将评估十字花科蔬菜在抑制与致癌有关的促炎信号通路中的作用，并将研究编码代谢ITC的酶的基因变异如何改变这些植物性食物对人类的影响。我们将在现有的随机对照饲养试验（R01 CA070913）中研究GSTM1和GSTT1基因型和十字花科蔬菜补充对特定饮食条件下nf - kb介导的血清炎症生物标志物的影响。目的是确定蔬菜饮食和十字花科蔬菜剂量是否对血清炎症生物标志物浓度有影响，并测量GSTM1和GSTT1基因型组合对生物标志物浓度的调节作用。我们有效地利用已收集的样品。根据GST基因型招募参与者，随机分为4种饮食：不含水果和蔬菜的基础饮食和在基础饮食中添加单剂量十字花科蔬菜的饮食；2)双剂量；3)十字花科+颖花类蔬菜。我们将在每个周期的第0、7和14天测量血清il - 12、IL-6、IL-10、TNF-1、sTNF RI和RII、CRP和SAA，并评估饮食和基因型的影响；并检查24小时尿ITC与这些生物标志物之间的关系。本研究结果将提高我们对十字花科蔬菜对人体NF-:B通路作用的认识，并将为遗传变异对反应的影响提供重要数据。

DESCRIPTION (provided by applicant): Consumption of cruciferous (i.e., broccoli-family) vegetables is associated with lower risk of several cancers, and is dependent, in part, on GSTM1/GSTT1 genotype. Isothiocyanates (ITC), the bioactive components derived from glucosinolates in crucifers, modulate enzymes that detoxify carcinogens and sex steroids, via activation of a transcription factor Nrf-2. Evidence also supports a role for ITC in another signaling pathway critical to carcinogenesis, inhibition of nuclear factor kappa-B (NF-kB). NF-kB is a transcription factor and central mediator in activation of genes involved in the inflammatory process, e.g., cytokines, chemokines, adhesion molecules and other soluble factors involved in the immune response. ITC inhibit NF-kB-mediated processes, and therefore may reduce inflammation -- a well-recognized risk factor of carcinogenesis. Higher levels of many cytokines have been associated with an increased risk of cancer. Variation in metabolism of ITC may influence ITC exposure and biologic response to these agents. Glutathione S-transferase (GST)M1 and GSTT1 metabolize ITC and genotypic differences in biologic response and ITC pharmacokinetics have been reported. However, it is not clear if the effects of these variants are on ITC metabolism or another unknown mechanism. There is a well-established literature on the modifying effects of GSTM1/GSTT1 genotypes in response to cruciferous vegetables; however the data are weak for other GST isoforms. Evidence suggests that activation of the transcription factor Nrf-2, as occurs with ITC, may diminish the pro- inflammatory cycle established via sustained NF-kB signaling. We will evaluate the role of cruciferous vegetables in inhibition of this pro-inflammatory signaling pathway relevant to carcinogenesis, and will address how variation in genes encoding enzymes that metabolize ITC alters effects of these plant foods in humans. We will examine, within our existing randomized, controlled feeding trial (R01 CA070913), effects of GSTM1 and GSTT1 genotypes and cruciferous vegetable supplementation on NF-kB-mediated serum inflammation biomarkers under defined-diet conditions. The aims are to determine whether there are effects of the vegetable diets and cruciferous-vegetable dose on serum inflammation biomarker concentrations and to measure the modifying effects of GSTM1 and GSTT1 genotype combinations on biomarker concentrations. We make efficient use of already collected samples. Participants were recruited based on GST genotype and randomized to 4 diets: a fruit- and vegetable-free basal diet and the basal diet supplemented with: 1) single- dose cruciferous vegetables; 2) a double-dose; and 3) cruciferous + apiaceous vegetables. We will measure serum IL12, IL-6, IL-10, TNF-1, sTNF RI and RII, CRP, and SAA on Days 0, 7, and 14 of each period and evaluate diet and genotype effects; and examine associations between 24-h urinary ITC and these biomarkers. Results of this study will improve our understanding of the action of cruciferous vegetables on the NF-:B pathway in humans and will provide important data as to the impact of genetic variation on response. PUBLIC HEALTH RELEVANCE: In order to make accurate public health recommendations it is important to understand more fully how specific types of vegetables, such as those in the broccoli and carrot families, affect certain processes involved in cancer prevention. Moreover, it is important to test if particular genetic characteristics augment or decrease the effect of these vegetables.