Absorption and metabolism of flavonoids in the Caco-2 cell culture model and a perfused rat intestinal model
Absorption and metabolism of flavonoids in the Caco-2 cell culture model and a perfused rat intestinal model
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DOI：
10.1124/dmd.30.4.370
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发表时间：
2002-04-01
影响因子：
3.9
通讯作者：
Hu, M
中科院分区：
文献类型：
--
作者：
Liu, Y;Hu, M
本研究的目的是确定染料木黄酮及其类似物的肠道吸收和代谢，以更好地了解其口服生物利用度低的机制。采用Caco-2细胞培养模型和大鼠肠灌流模型进行研究。在这两种模型中，糖苷配基的渗透性（例如，染料木黄酮）与吸收良好的化合物如睾酮和普萘洛尔相当。在Caco-2模型中，糖苷配基的渗透性比其相应的糖苷（例如，染料木苷元的载体转运相似（p > 0.05）。相反，葡萄糖苷的载体转运有利于排泄（p < 0.05）。在Caco-2模型中观察到糖苷的有限水解，其被20 mM藜芦内酯（一种广泛特异性糖苷酶抑制剂）完全抑制（p < 0.05）。在灌流大鼠肠道模型中，染料木苷在上肠中迅速水解（15分钟内约40%），但在结肠中完全不水解。糖苷配基被迅速吸收（P*（eff）> 1.5），吸收的糖苷配基在小肠上部通过葡萄糖醛酸化和硫酸化进行广泛的（最大40%）II相代谢。与水解相似，结合染料木黄酮的回收率也具有区域依赖性，空肠最高，结肠最低（p < 0.05）。结合物回收率的这种差异可能是由于酶或外排转运蛋白活性的差异，研究结果倾向于表明这两种因素都参与其中。总之，染料木黄酮及其类似物在两种肠道模型中吸收良好，因此，吸收不良不是其生物利用度低的原因。另一方面，肠内广泛的II相代谢显著导致其生物利用度低。
The purpose of present study was to determine the intestinal absorption and metabolism of genistein and its analogs to better understand the mechanisms responsible for their low oral bioavailability. The Caco-2 cell culture model and a perfused rat intestinal model were used for the study. In both models, permeabilities of aglycones (e.g., genistein) were comparable to well absorbed compounds, such as testosterone and propranolol. In the Caco-2 model, permeabilities of aglycones were at least 5 times higher (p < 0.05) than their corresponding glycosides (e.g., genistin), and the vectorial transport of aglycones was similar (p > 0.05). In contrast, vectorial transport of glucosides favored excretion (p < 0.05). Limited hydrolysis of glycosides was observed in the Caco-2 model, which was completely inhibited (p < 0.05) by 20 mM gluconolactone, a broad specificity glycosidase inhibitor. In the perfused rat intestinal model, genistin was rapidly hydrolyzed (about 40% in 15 min) in the upper intestine but was not hydrolyzed at all in the colon. Aglycones were rapidly absorbed (P*(eff) > 1.5), and absorbed aglycones underwent extensive (40% maximum) phase II metabolism via glucuronidation and sulfation in the upper small intestine. Similar to the hydrolysis, recovery of conjugated genistein was also region-dependent, with jejunum having the highest and colon the lowest (p < 0.05). This difference in conjugate recovery could be due to the difference in the activities of enzymes or efflux transporters, and the results of studies tend to suggest that both of these factors were involved. In conclusion, genistein and its analogs are well absorbed in both intestinal models, and therefore, poor absorption is not the reason for its low bioavailability. On the other hand, extensive phase II metabolism in the intestine significantly contributes to its low bioavailability.