Cruciferous vegetable feeding and inflammation: effect of GST genotypes

说明(申请人提供)：食用十字花科(即西兰花科)蔬菜与较低的几种癌症风险有关，部分取决于GSTM1/GSTT1基因。异硫氰酸酯(ITC)是十字花科植物中从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来调节酶对致癌物和性类固醇的解毒作用。证据也支持ITC在另一条致癌关键的信号通路中的作用，即抑制核因子kappaB(NF-kB)。核因子-kB是参与炎症过程的细胞因子、趋化因子、黏附分子和其他参与免疫反应的可溶性因子等参与炎症过程的基因激活的转录因子和中枢调节因子。ITC抑制核因子-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患癌症的风险增加有关。ITC代谢的变化可能会影响ITC的暴露和对这些制剂的生物反应。谷胱甘肽S转移酶M1和GSTT1代谢ITC，已有报道在生物反应和ITC的药代动力学方面存在基因差异。然而，目前尚不清楚这些变异是否影响ITC的新陈代谢或其他未知机制。关于GSTM1/GSTT1基因对十字花科蔬菜的修饰作用，已经有了成熟的文献；然而，对于其他GST亚型的数据很弱。有证据表明，转录因子NRF-2的激活，就像ITC所发生的那样，可能会减少通过持续的NF-kB信号建立的促炎循环。我们将评估十字花科蔬菜在抑制这一与致癌相关的促炎信号通路中的作用，并将讨论编码代谢ITC的酶的基因变异如何改变这些植物食品对人类的影响。我们将在我们现有的随机控制喂养试验(R01 CA070913)中，研究在限定饮食条件下，GSTM1和GSTT1基因型以及十字花科蔬菜补充对NF-kB介导的血清炎症生物标志物的影响。目的是确定蔬菜日粮和十字花科蔬菜剂量是否对血清炎症生物标记物浓度有影响，以及GSTM1和GSTT1基因组合对生物标记物浓度的调节作用。我们有效地利用了已经收集的样本。受试者根据GST基因型被招募，并随机分为4种饮食：不含水果和蔬菜的基础饮食和基础饮食中添加：1)单剂十字花科蔬菜；2)双剂量；3)十字花科+蜂类蔬菜。我们将在每个周期的第0、7和14天检测血清IL12、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与这些生物标志物的相关性。这项研究的结果将加深我们对十字花科蔬菜在人类核因子：B途径中的作用的理解，并将为遗传变异对反应的影响提供重要的数据。 与公共健康相关：为了提出准确的公共健康建议，重要的是更充分地了解特定类型的蔬菜，如花椰菜和胡萝卜家族中的蔬菜，如何影响涉及癌症预防的某些过程。此外，重要的是要测试特定的遗传特征是否会增强或减少这些蔬菜的影响。

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.