Methylation of dietary flavones greatly improves their hepatic metabolic stability and intestinal absorption.
Methylation of dietary flavones greatly improves their hepatic metabolic stability and intestinal absorption.
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DOI：
10.1021/mp700071d
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发表时间：
2007-10
影响因子：
4.9
通讯作者：
T. Walle
中科院分区：
文献类型：
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作者：
T. Walle
饮食中的类黄酮和其他多酚具有许多生物学特性，可以作为化学预防药物使用。然而，非常差的口服生物利用度使它们在体内很大程度上无效。生物利用度低的主要原因是这些单羟基或多羟基的药物在肠道/肝脏屏障中高效地结合了葡萄糖醛酸和硫酸盐。这篇综述描述了当代谢转移到低效的CYP介导的氧化时，如何使所有游离羟基的甲基封端导致代谢稳定性显著提高。这一点通过使用人肝S9组分和适当的辅因子选择得到了最好的证明。此外，Caco-2细胞Transwell实验表明，通过甲基化大大改善了黄酮类化合物的肠道转运。在大鼠体内，口服一个甲基化的黄酮会导致高的生物利用度和组织分布，没有检测到其未甲基化类似物的水平。除了提高代谢稳定性外，甲基化还显著增强了对癌细胞增殖的抑制作用。因此，甲基化似乎是一种简单而有效的方法，可以增加类黄酮的代谢阻力和转运，最重要的是，增加它们的一些主要生物活性。
Dietary flavonoids and other polyphenols have many biological properties that could make them useful as chemopreventive agents. However, very poor oral bioavailability makes them largely ineffective in vivo. The low bioavailability is mainly due to highly efficient glucuronic acid and sulfate conjugation of these mono- or polyhydroxylated agents in the intestinal/hepatic barrier. This review describes how the methyl capping of all free hydroxyl groups of flavones results in dramatically increased metabolic stability, as the metabolism is shifted to less efficient CYP-mediated oxidation. This was demonstrated best by using the human liver S9 fraction with an appropriate selection of cofactors. In addition, the intestinal transport of flavones was much improved through methylation, as shown in Caco-2 cell Transwell experiments. In vivo in the rat, oral administration of one methylated flavone resulted in high bioavailability and tissue distribution with no detectable levels of its unmethylated analogue. In addition to increased metabolic stability, methylation resulted in markedly increased inhibition of cancer cell proliferation. Thus, methylation appears to be a simple and effective way of increasing both metabolic resistance and transport of the flavonoids and, most important, some of their major biological activities.