Cruciferous vegetable feeding and inflammation: effect of GST genotypes

十字花科蔬菜取食与炎症：GST 基因型的影响

• 批准号: 7983138
• 负责人: JOHANNA W LAMPE
• 金额: $ 26.03万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7983138
• 关键词: Address; Affect; Biological Markers; Broccoli - dietary; C-reactive protein; Carcinogenesis Inhibition; Carcinogens; Carrots - dietary; Cell Adhesion Molecules; Cell Cycle Arrest; Characteristics; Consumption; Cytochrome P450; Data; Diet; Dose; Drug Kinetics; Edible Plants; Enzyme Activation; Enzymes; Excretory function; Family; GSTM1 gene; GSTT1 gene; Gene Activation; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Glucosinolates; Glutathione S-Transferase; Goals; Gonadal Steroid Hormones; Human; Immune response; In Vitro; Inflammation; Inflammatory; Inhibition of Apoptosis; Interleukin-10; Interleukin-12; Interleukin-24; Interleukin-6; Interleukins; Intervention; Isothiocyanates; Knowledge; Lead; Literature; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Metabolic Biotransformation; Metabolism; NF-kappa B; Outcome; Participant; Pathway interactions; Phase; Positioning Attribute; Process; Protein Isoforms; Public Health; Randomized; Recommendation; Recruitment Activity; Reporting; Risk; Risk Factors; Role; Sampling; Serum; Serum amyloid A protein; Signal Pathway; Signal Transduction; Study Section; Supplementation; TNFR-Fc fusion protein; Testing; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; UDP-Glucuronosyltransferase 1A1; Variant; Vegetables; base; cancer prevention; cancer risk; carcinogenesis; chemokine; cruciferous vegetable; cytokine; design; dietary constituent; dietary control; dietary supplements; feeding; fruits and vegetables; genetic variant; improved; inflammatory marker; nuclear factor-erythroid 2; public health relevance; response; transcription factor; urinary

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.

描述（由申请人提供）：十字花科（即西兰花家庭）蔬菜的消费与多种癌症的较低风险有关，并且部分取决于GSTM1/GSTT1基因型。异硫氰酸盐（ITC），是crucifer中葡萄糖醇的生物活性成分，通过激活转录因子NRF-2的激活来调节将癌和性类固醇解毒的酶。证据还支持ITC在对癌变至关重要的另一个信号通路中的作用，抑制核因子Kappa-B（NF-KB）。 NF-KB是炎症过程中涉及基因激活的转录因子和中心介体，例如细胞因子，趋化因子，粘附分子和其他参与免疫反应的可溶性因子。 ITC抑制NF-KB介导的过程，因此可能减少炎症 - 癌变的众所周知的危险因素。许多细胞因子的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。已经报道了谷胱甘肽S-转移酶（GST）M1和GSTT1代谢ITC以及生物反应中的基因型差异和ITC药代动力学的基因型差异。但是，尚不清楚这些变体的影响是否对ITC代谢或其他未知机制。有关于GSTM1/GSTT1基因型对十字花科蔬菜的修改作用的知名文献。但是，其他GST同工型的数据较弱。证据表明，与ITC发生的转录因子NRF-2的激活可能会减少通过持续的NF-KB信号建立的炎症周期。我们将评估十字花科蔬菜在抑制与癌变有关的促炎信号传导途径中的作用，并将解决编码代谢ITC的酶的变异，以改变这些植物性食物在人类中的影响。我们将在我们现有的随机对照喂养试验（R01 CA070913）中检查GSTM1和GSTT1基因型的影响，以及在定义的diet条件下对NF-KB介导的血清炎症生物标志物对NF-KB介导的血清炎症生物标志物的影响。目的是确定蔬菜饮食和十字花科植被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修饰作用。我们有效利用已经收集的样品。基于GST基因型招募参与者，并随机分为4种饮食：一种无水果和蔬菜的基础饮食以及补充的基础饮食：1）单剂量十字花科蔬菜； 2）双剂量；和3）十字花科 +阿皮斯蔬菜。我们将在每个时期的第0、7和14天测量血清IL12，IL-6，IL-10，TNF-1，STNF RI和RII，CRP和SAA，并评估饮食和基因型影响；并检查24小时尿ITC与这些生物标志物之间的关联。这项研究的结果将提高我们对人类NF-：B途径的作用的理解，并将提供有关遗传变异对反应的影响的重要数据。 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（例如西兰花和胡萝卜家庭中的蔬菜）如何影响预防癌症的某些过程。此外，重要的是要测试特定的遗传特征是增加或减少这些蔬菜的影响。