Intestinal tract as an organ for detoxification and excretion-Molecular analyses of its regulation by food factors

第一阶段酶（CYP等）、第二阶段酶（UGT等）和第三阶段转运蛋白（MDR、MRP等）参与肠道的解毒和排泄功能。本研究对调节这些功能的食物因子进行了筛选和分子分析。利用人肠上皮细胞体外实验系统，在多种食品材料中寻找直接影响MDR1的调控因子。例如，2-单铝酸盐被确定为一种抑制MDR1活性的饮食因子。由于已知PXR参与解毒的调节，因此使用报告基因法寻找可激活核受体PXR的食物因子。某些类黄酮和萜类化合物被发现可以激活PXR，从而在mRNA、蛋白和活性水平上刺激MDR1的表达。我们还发现某些黄酮类化合物和萜类化合物分别抑制ahr介导和pxr介导的Phase 1酶的表达。此外，还发现更多的酶受黄酮类、萜类、氨基酸、异黄酮及其代谢物的调控。食物因子对解毒酶CYP1A1、UGT1A1、MDR1和MRP2基因表达的诱导表现出不同的模式。这表明，食物因素多种多样地协同影响肠道的解毒和外排过程。观察到食物因子与某些转录因子的直接结合参与了这种解毒过程，转录因子向细胞核的转移伴随着这种结合。我们还发现，解毒系统在食物物质的生理功能表达中起着重要作用，说明解毒酶不仅具有解毒和消除有害物质的作用，还具有增强食物因子生理功能的作用。该项目还提出了膳食物质通过刺激排毒系统来调节肠道屏障系统的重要性。少

Phase 1 enzymes (CYP etc.), Phase 2 enzymes (UGT etc.), and Phase 3 transporters (MDR, MRP etc.) are involved in detoxification and excretion functions of the gut. Screening and molecular analyses of the food factors which regulate these functions were performed in this study. Regulatory factors which directly affect MDR1 were searched in a variety of food materials by using in vitro experimental systems with human intestinal epithelial cells. 2-monopalmitate, for example, was identified as a dietary factor which inhibit MDR1 activity. Food factors that would activate a nuclear receptor PXR were searched by using reporter assay, because PXR is known to be involved in the regulation of detoxification. Certain flavonoids and terpenoids were found to activate PXR, thereby stimulating the expression of MDR1 at mRNA, protein and activity levels. We also found certain flavonoids and terpenoids suppressed the AhR-mediated and PXR-mediated expression of Phase 1 enzymes, respectively. Phase 2 e … More nzymes were also found to be regulated by flavonoids, terpenoids, amino acids, isoflavones and their metabolites. Induction by food factors of gene expression for detoxification enzymes such as CYP1A1, UGT1A1, MDR1 and MRP2 showed various patterns depending on the food factors. This suggests that food factors diversely and cooperatively affect the detoxification and efflux processes in the gut. Direct binding of food factors with certain transcription factors was observed to be involved in this detoxification process, transfer of the transcription factors to the nuclei being accompanied with this binding. We have also found that the detoxification system plays an important role in the expression of physiologic functions of food substances, suggesting that the detoxificating enzymes are not only for the detoxification and elimination of harmful substances, but also for enhancing the physiologic functions of food factors. The importance of dietary substances in regulating the intestinal barrier system by stimulating the detoxification system is also suggested by this project. Less