Effects of diammonium glycyrrhizinate on hepatic and intestinal UDP-Glucuronosyltransferases in rats: Implication in herb-drug interactions
Effects of diammonium glycyrrhizinate on hepatic and intestinal UDP-Glucuronosyltransferases in rats: Implication in herb-drug interactions
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DOI：
10.1016/s1875-5364(16)30063-2
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发表时间：
2016-07-01
影响因子：
4.6
通讯作者：
Wang Guang-Ji
中科院分区：
文献类型：
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作者：
Li Fei-Yan;Xie Hao;Wang Guang-Ji
甘草甜素是甘草的主要活性成分，具有多种生物化学和药理活性，临床上常与其他药物联用。霉酚酸酯（MMF）是一种广泛用于移植患者的免疫抑制剂，通过UDP-葡萄糖醛酸转移酶（UGT）代谢。尽管有大量证据支持甘草酸可以与细胞色素P450（CYP）相互作用，但很少有研究讨论其对UGT的影响。本研究旨在研究甘草酸二铵（GLN）在体内外对UGT的调节作用。我们发现，大鼠长期给予GLN诱导了MMF的整体代谢，这可能是由于UGT 1A蛋白表达的诱导。GLN处理组大鼠肝脏UGT 1A活性、UGT 1A mRNA和蛋白表达均显著增加。UGT 1A表达水平也在肠道中增加，与观察到的肠道UGT 1A活性降低相矛盾。这可能是由于大黄酸（GA）在肝和肠中的浓度不同以及GA对UGT 1A活性的抑制作用所致。总之，我们的研究表明，GLN对UGT 1A亚型的表达和活性具有多重影响，为更好地理解GLN与其他药物之间的相互作用提供了基础。
Glycyrrhizin is a major bioactive component of liquorice, which exerts multiple biochemical and pharmacological activities and is frequently used in combination with other drugs in the clinic. Mycophenolate mofetil (MMF), an immunosuppressant widely used in transplant patients, is metabolized by UDP-glucuronyltransferases (UGTs). Although significant evidence supports that glycyrrhizin could interact with the cytochrome P450s (CYPs), few studies have addressed its effects on UGTs. The present study aimed at investigating the regulatory effects of diammonium glycyrrhizinate (GLN) on UGTs in vitro and in vivo. We found that long-term administration of GLN in rats induced overall metabolism of MMF, which might be due to the induction of UGT1A protein expression. Hepatic UGT1A activity and UGT1A mRNA and protein expression were significantly increased in GLN-treated rats. UGT1A expression levels were also increased in the intestine, contradicting with the observed decrease in intestinal UGT1A activities. This phenomenon may be attributed to different concentrations of glycyrrhetinic acid (GA) in liver and intestine and the inhibitory effects of GA on UGT1A activity. In conclusion, our study revealed that GLN had multiple effects on the expression and activities of UGT1A isoforms, providing a basis for a better understanding of interactions between GLN and other drugs.