Dietary Regulation of Biochemical/Molecular Changes

生化/分子变化的饮食调节

• 批准号: 6949460
• 负责人: GRACE YEH
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6949460
• 关键词: NAD(H) phosphate; benzoates; benzopyrenes; cancer prevention; carcinogens; chemical carcinogenesis; chemoprevention; cytoprotection; enzyme activity; gene environment interaction; gene expression; genetic transcription; glucose 6 phosphate dehydrogenase; nutrition aspect of cancer; nutrition related tag; oxidative stress; stilbenes; tissue /cell culture; toxin metabolism

Phase I enzymes like CYP1A1 and Phase 2 enzymes such as quinone reductase use NADPH as a reducing co-factor. NADPH, the major cellular source of reducing power, is generated by the pentose-phosphate pathway, which converts glucose-6-phosphate into NADPH and ribose. NADPH, in addition to serving as a cofactor for the enzymes listed above, also serves as a co-factor in the synthesis of reduced glutathione by glutathione reductase. Thus, this pathway is a central pathway in cellular defense against carcinogens and oxidant stress. The key regulator of this pathway, and therefore of NADPH levels, is glucose-6-phosphate dehydrogenase (G6PD). This enzyme has long been thought to be a "housekeeping" gene that is constitutively expressed. However, recent studies have demonstrated that G6PD is, in fact, highly regulated and inducible. We have investigated changes in G6PD activity and expression in vitro in response to xenobiotics. We found that long term exposure of cells to the carcinogen benzo[a]pyrene caused an increase in the expression and activity of G6PD. This was not due to modulation of gene transcription, but was due to a post-transcriptional stabilization of G6PD mRNA. We have also found that certain dietary phytochemicals such as dibenzoylmethane and resveratrol increase the expression of G6PD by increasing gene transcription. We are currently examining how this activation occurs. Such increases in G6PD expression would be protective against carcinogens as well as oxidative stress in that it would increase the cell's antioxidant capacity.

第一阶段酶如CYP1A1和第二阶段酶如醌还原酶使用NADPH作为还原辅助因子。NADPH是细胞还原能力的主要来源，由戊糖-磷酸途径产生，将葡萄糖-6-磷酸转化为NADPH和核糖。NADPH除了作为上述酶的辅助因子外，还作为谷胱甘肽还原酶合成还原性谷胱甘肽的辅助因子。因此，该途径是细胞防御致癌物和氧化应激的中心途径。葡萄糖-6-磷酸脱氢酶（葡萄糖-6-磷酸脱氢酶，G6PD）是这一途径的关键调节因子，因此也是NADPH水平的关键调节因子。这种酶一直被认为是一种组成性表达的“管家”基因。然而，最近的研究表明，G6PD实际上是高度调控和诱导的。我们研究了G6PD活性和体外表达在外源药物作用下的变化。我们发现，细胞长期暴露于致癌物苯并[a]芘中会导致G6PD的表达和活性增加。这不是由于基因转录的调节，而是由于G6PD mRNA的转录后稳定。我们还发现，某些膳食植物化学物质，如二苯甲酰甲烷和白藜芦醇，通过增加基因转录增加G6PD的表达。我们目前正在研究这种激活是如何发生的。这种G6PD表达的增加将对致癌物质和氧化应激有保护作用，因为它会增加细胞的抗氧化能力。