Dietary Regulation of Biochemical/Molecular Changes

I相酶如CYP 1A 1和2相酶如醌还原酶使用NADPH作为还原辅因子。还原力的主要细胞来源NADPH是由戊糖-磷酸途径产生的，该途径将葡萄糖-6-磷酸转化为NADPH和核糖。NADPH除了作为上述酶的辅因子外，还作为谷胱甘肽还原酶合成还原型谷胱甘肽的辅因子。因此，该途径是细胞防御致癌物和氧化应激的中心途径。该途径的关键调节物，以及因此NADPH水平的关键调节物是葡萄糖-6-磷酸脱氢酶（G6 PD）。这种酶长期以来被认为是组成型表达的“管家”基因。然而，最近的研究表明，G6 PD实际上是高度调节和诱导的。我们已经研究了G6 PD活性和表达的变化，在体外对外源性物质的反应。我们发现，细胞长期暴露于致癌物苯并[a]芘导致G6 PD的表达和活性增加。这不是由于基因转录的调节，而是由于G6 PD 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来增加G6 PD的表达。我们目前正在研究这种激活是如何发生的。G6 PD表达的这种增加将对致癌物以及氧化应激具有保护作用，因为它将增加细胞的抗氧化能力。

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.