Metabolism of flavonoids via enteric recycling: Mechanistic studies of disposition of apigenin in the Caco-2 cell culture model
Metabolism of flavonoids via enteric recycling: Mechanistic studies of disposition of apigenin in the Caco-2 cell culture model
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DOI：
10.1124/jpet.103.053496
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发表时间：
2003-10-01
影响因子：
3.5
通讯作者：
Lin, HM
中科院分区：
文献类型：
--
作者：
Hu, M;Chen, J;Lin, HM
本研究的目的是确定芹菜素在人Caco-2细胞培养模型中肠道处置的机制。结果表明，大部分吸收的芹菜素（10 μ M）的共轭和只有一小部分被完整的运输。结合物的排泄量，特别是硫酸盐的排泄量，取决于接种后的天数。芹菜素硫酸盐的顶端流出量不随芹菜素浓度（4 - 40 μ M）而变化，而其基底外侧流出量随浓度增加（p < 0.01），并在约25 μM时达到稳定。相比之下，细胞裂解物中的硫酸盐形成速率随浓度增加而增加，并在25 μM时达到平台，比相应的排泄速率快4至6倍。葡萄糖醛酸化芹菜素的形成和极化排泄率随着芹菜素浓度的增加而增加，但形成率通常比相应的排泄率快2.5至6倍。多药耐药相关蛋白（MRP）抑制剂（如白三烯C-4和MK-571）在高浓度（≥25 μM）下可抑制芹菜素的葡萄糖醛酸化，显著降低两种芹菜素结合物的排泄，较高浓度的MK-571可增加抑制程度。相反，有机阴离子转运蛋白（OAT）抑制剂硫酸雌酮只抑制硫酸芹菜素的排泄。总之，我们已经表明，第一次，肠外排是在肠道排泄的II相结合的黄酮类化合物的限速步骤。此外，MRP和OAT参与这些亲水性II相缀合物的肠外排。
The purpose of this study was to determine the mechanisms responsible for intestinal disposition of apigenin in the human Caco-2 cell culture model. The results indicated that most of the absorbed apigenin (10 muM) were conjugated and only a small fraction was transported intact. The amounts of conjugates excreted, especially that of the sulfate, were dependent on days-post-seeding. Apical efflux of apigenin sulfate did not change with concentration of apigenin (4 to 40 muM), whereas its basolateral efflux increased (p < 0.01) with concentration and plateaued at about 25 μM. In contrast, sulfate formation rates in cell lysate increased with concentration and plateaued at 25 μM and were 4 to 6 times faster than the corresponding excretion rates. Formation and polarized excretion rates of glucuronidated apigenin increased with apigenin concentration but formation rates were usually 2.5 to 6 times faster than the corresponding excretion rates. Inhibitors of multidrug resistance-related proteins (MRPs) such as leukotriene C-4 and MK-571, which inhibited glucuronidation of apigenin at a high concentration (≥25 μM), significantly decreased excretion of both apigenin conjugates, and higher concentrations of MK-571 increased the extent of inhibition. In contrast, an organic anion transporter (OAT) inhibitor estrone sulfate only inhibited excretion of apigenin sulfate. In conclusion, we have shown for the first time that intestinal efflux is the rate-limiting step in the intestinal excretion of phase II conjugates of flavones. Furthermore, MRP and OAT are involved in the intestinal efflux of these hydrophilic phase II conjugates.