Potent and selective inhibition of magnolol on catalytic activities of UGT1A7 and 1A9
Potent and selective inhibition of magnolol on catalytic activities of UGT1A7 and 1A9
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厚朴酚对 UGT1A7 和 1A9 催化活性的有效选择性抑制
DOI：
10.3109/00498254.2012.681814
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发表时间：
2012-10-01
期刊：
影响因子：
1.8
通讯作者：
Yang, Ling
中科院分区：
文献类型：
--
作者：
Zhu, Liangliang;Ge, Guangbo;Yang, Ling
在日常生活中，人类接触到厚朴酚的剂量可能会很高。我们以前的研究表明，厚朴酚对几种UDP-葡萄糖醛酸基转移酶(UGTS)具有很高的亲和力。本研究旨在检测厚朴酚对UGTS的体外抑制作用，并进一步评估其体内抑制作用的可能性。用重组UGTS和人肝微粒体(HLM)检测表明，厚朴酚(10µM)能选择性抑制UGT1A9和肝外UGT1A7的活性。厚朴酚对UGT1A7的抑制遵循竞争抑制机制，而对UGT1A9的抑制根据底物的不同而遵循竞争或混合抑制机制。UGT1A7和1A9的Ki值均在纳摩尔范围内，低于人体肠腔和血液中厚朴酚的可能浓度，表明这两种酶可能在体内受到抑制。综上所述，厚朴酚对UGT1A7和1A9有较强的抑制作用，为厚朴酚及含厚朴酚中药的安全应用提出了警示。此外，鉴于UGT1A7是一种肝外酶，厚朴酚可以作为一种选择性的UGT1A9抑制剂，将在未来的肝脏葡萄糖醛酸化表型中作为一种新的有用工具。
Human exposure to magnolol can reach a high dose in daily life. Our previous studies indicated that magnolol showed high affinities to several UDP-glucuronosyltransferases (UGTs) This study was designed to examine the in vitro inhibitory effects of magnolol on UGTs, and further to evaluate the possibility of the in vivo inhibition that might happen. Assays with recombinant UGTs and human liver microsomes (HLM) indicated that magnolol (10 µM) can selectively inhibit activities of UGT1A9 and extra-hepatic UGT1A7. Inhibition of magnolol on UGT1A7 followed competitive inhibition mechanism, while the inhibition on UGT1A9 obeyed either competitive or mixed inhibition mechanism, depending on substrates. The Ki values for UGT1A7 and 1A9 are all in nanomolar ranges, lower than possible magnolol concentrations in human gut lumen and blood, indicating the in vivo inhibition on these two enzymes would likely occur. In conclusion, UGT1A7 and 1A9 can be strongly inhibited by magnolol, raising the alarm for safe application of magnolol and traditional Chinese medicines containing magnolol. Additionally, given that UGT1A7 is an extra-hepatic enzyme, magnolol can serve as a selective UGT1A9 inhibitor that will act as a new useful tool in future hepatic glucuronidation phenotyping.