Disposition of Flavonoids via Enteric Recycling: UDP-Glucuronosyltransferase (UGT) 1As Deficiency in Gunn Rats Is Compensated by Increases in UGT2Bs Activities
Disposition of Flavonoids via Enteric Recycling: UDP-Glucuronosyltransferase (UGT) 1As Deficiency in Gunn Rats Is Compensated by Increases in UGT2Bs Activities
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DOI：
10.1124/jpet.108.147371
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发表时间：
2009-06-01
影响因子：
3.5
通讯作者：
Hu, Ming
中科院分区：
文献类型：
--
作者：
Wang, Stephen W. J.;Kulkarni, Kaustubh H.;Hu, Ming
黄酮类化合物的生物利用度较低，主要是由于通过UDP-葡萄糖醛酸基转移酶(UGTS)进行代谢。本研究旨在进一步了解UGT在代谢染料木素和芹菜素中的功能，这两种化合物在肠道中的代谢范围比在肝脏中更广泛。由于Gunn大鼠缺乏UGT1As，我们利用大鼠肠道灌流模型和大鼠肝脏和肠道制备的微粒体来确定这种缺乏是否会导致黄酮类葡萄糖醛酸化作用的减少。在酵母表达的大鼠UGT亚型中，大鼠UGT1A亚型(尤其是UGT1A7)主要负责类黄酮类的代谢。在灌流研究中，这两种黄酮类化合物以相当的速度被迅速吸收，但Gunn大鼠与Wistar大鼠相比，Gunn大鼠的肠道分泌的葡萄糖醛酸苷不仅与Genistein相似，而且对芹菜素的含量更高(p<；0.05)，提示Gunn大鼠的UGT亚型上调。为了确定可能的代偿UGT亚型，我们首先用UGT1A特异的探针7-乙基-10-羟基喜树碱(SN-38)和梅花素验证了Gunn大鼠的UGT1A活性显著降低(p<；0.05)。然后，我们使用UGT2B探针证明了睾酮、依折麦布和消炎痛在Gunn大鼠中的UGT2B活性通常显著更高。此外，与Wistar大鼠相比，Gunn大鼠和Wistar大鼠的肝脏微粒体中睾酮的代谢速度要快得多。总之，由于肠道UGT2B和肝脏阴离子外流转运体的代偿性上调，UGT1a缺陷的Gunn大鼠可以有效地代谢黄酮类化合物，这增加了它们的处置能力，限制了它们的口服生物利用度。
Flavonoids have poor bioavailabilities largely because of metabolism via UDP-glucuronosyltransferases (UGTs). This study aims to further understand the functions of UGT in metabolizing genistein and apigenin, two compounds metabolized more extensively in the gut than in the liver. Because Gunn rats are deficient in UGT1As, we determined whether this deficiency would result in less flavonoid glucuronidation, using rat intestinal perfusion model and microsomes prepared from rat liver and intestine. In yeast-expressed rat UGT isoforms, rat UGT1A isoforms (especially UGT1A7) were mainly responsible for flavonoid metabolism. In perfusion studies, the two flavonoids were rapidly absorbed at comparable rates, but the intestinal excretions of glucuronides in Gunn rats compared with Wistar rats were not only comparable for genistein but also were higher (p < 0.05) for apigenin, suggesting up-regulation of UGT isoforms in Gunn rats. To determine the possible compensatory UGT isoforms, we first verified that UGT1A activities were significantly lower (p < 0.05) in Gunn rats by using UGT1A-specific probes 7-ethyl-10-hydroxycamptothecin (SN-38) and prunetin. We then demonstrated using UGT2B probes testosterone, ezetimibe, and indomethacin that UGT2B activities were usually significantly higher in Gunn rats. In addition, testosterone was metabolized much faster in liver microsomes than in intestinal microsomes, and in microsomes prepared from Gunn rats compared with Wistar rats. In conclusion, flavonoids are efficiently metabolized by UGT1A-deficient Gunn rats because of compensatory up-regulation of intestinal UGT2Bs and hepatic anion efflux transporters, which increases their disposition and limits their oral bioavailabilities.