Cruciferous vegetable feeding and inflammation: effect of GST genotypes

描述（由申请人提供）：食用十字花科植物（即，西兰花家族）蔬菜与几种癌症的低风险相关，并且部分依赖于GSTM 1/GSTT 1基因型。异硫氰酸酯（ITC）是十字花科植物中硫代葡萄糖苷的生物活性成分，通过激活转录因子Nrf-2来调节解毒致癌物和性类固醇的酶。证据还支持ITC在另一种对致癌作用至关重要的信号通路中发挥作用，即抑制核因子kappa-B（NF-kB）。NF-kB是一种转录因子，也是参与炎症过程的基因激活的中心介质，细胞因子、趋化因子、粘附分子和其他参与免疫应答的可溶性因子。ITC抑制NF-kB介导的过程，因此可以减少炎症-一种公认的致癌风险因素。许多细胞因子的高水平与癌症风险增加有关。ITC代谢的变化可能会影响ITC暴露和生物反应。谷氨酰胺S-转移酶（GST）M1和GSTT 1代谢ITC和生物反应和ITC药代动力学的基因型差异已被报道。然而，目前尚不清楚这些变体的影响是否是对ITC代谢或其他未知机制的影响。关于GSTM 1/GSTT 1基因型对十字花科蔬菜的修饰作用有一个成熟的文献;然而，其他GST亚型的数据很弱。有证据表明，转录因子Nrf-2的激活，如ITC所发生的，可能会减少通过持续的NF-κ B信号传导建立的促炎循环。我们将评估十字花科蔬菜在抑制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的酶的基因的变异如何改变这些植物性食物对人类的影响。我们将在我们现有的随机对照喂养试验（R 01 CA 070913）中研究GSTM 1和GSTT 1基因型和十字花科蔬菜补充剂在规定饮食条件下对NF-κ B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GSTM 1和GSTT 1基因型组合对生物标志物浓度的修饰作用。我们有效地利用已经收集的样本。基于GST基因型招募参与者，并将其随机分配至4种饮食：无水果和蔬菜的基础饮食和补充有以下各项的基础饮食：1）单剂量十字花科蔬菜; 2）双剂量;和3）十字花科+芹菜类蔬菜。我们将在每个阶段的第0天、第7天和第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效应;并检查24小时尿ITC与这些生物标志物之间的相关性。这项研究的结果将提高我们的十字花科蔬菜对NF-：B途径在人类的行动的理解，并将提供重要的数据，遗传变异的影响的反应。 公共卫生相关性：为了提出准确的公共卫生建议，重要的是要更充分地了解特定类型的蔬菜，如西兰花和胡萝卜家族中的蔬菜，如何影响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加或减少这些蔬菜的效果。

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.