Guo Bin, Fang Zhongze, Yang Lu, Xiao Ling, Xia Yangliu, Gonzalez Frank J, Zhu Liangliang, Cao Yunfeng, Ge Guangbo, Yang Ling, Sun Hongzhi
The First Affiliated Hospital of Liaoning Medical University, Jinzhou, China; Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences and The First Affiliated Hospital of Liaoning Medical University, Dalian, China.
Department of Toxicology, School of Public Health, Tianjin Medical University, Tianjin, China; Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences and The First Affiliated Hospital of Liaoning Medical University, Dalian, China.
Chem Biol Interact. 2015 Apr 25;231:90-7. doi: 10.1016/j.cbi.2015.03.001. Epub 2015 Mar 9.
Glabridin (GA) has gained wide application in the cosmetics and food industry. This study was performed to investigate its metabolic inactivation and elimination by glucuronidation by use of liver and intestine microsomes from humans (HLM and HIM) and rats (RLM and RIM), and liver microsomes from cynomolgus monkeys and beagle dogs (CyLM and DLM). Both hydroxyl groups at the C2 and C4 positions of the B ring are conjugated to generate two mono-glucuronides (M1 and M2). HIM, RIM and RLM showed the most robust activity in catalyzing M2 formation with intrinsic clearance values (Clint) above 2000 μL/min/mg, with little measurable M1 formation activity. DLM displayed considerable activity both in M1 and M2 formation, with Clint values of 71 and 214 μL/min/mg, respectively, while HLM and CyLM exhibited low activities in catalyzing M1 and M2 formation, with Clint values all below 20 μL/min/mg. It is revealed that UGT1A1, 1A3, 1A9, 2B7, 2B15 and extrahepatic UGT1A8 and 1A10 are involved in GA glucuronidation. Nearly all UGTs preferred M2 formation except for UGT1A1. Notably, UGT1A8 displayed the highest activity with a Clint value more than 5-fold higher than the other isoforms. Chemical inhibition studies, using selective inhibitors of UGT1A1, 1A9, 2B7 and 1A8, further revealed that UGT1A8 contributed significantly to intestinal GA glucuronidation in humans. In summary, this in vitro study demonstrated large species differences in GA glucuronidation by liver and intestinal microsomes, and that intestinal UGTs are important for the pathway in humans.
光甘草定（GA）已在化妆品和食品工业中得到广泛应用。本研究旨在利用人（HLM和HIM）和大鼠（RLM和RIM）的肝脏和肠道微粒体以及食蟹猴和比格犬的肝脏微粒体（CyLM和DLM），研究其通过葡萄糖醛酸化作用的代谢失活和消除情况。B环C2和C4位的两个羟基发生共轭反应生成两种单葡萄糖醛酸苷（M1和M2）。HIM、RIM和RLM在催化M2形成方面表现出最强的活性，内在清除率（Clint）值高于2000 μL/min/mg，几乎没有可测量的M1形成活性。DLM在M1和M2形成方面均表现出相当的活性，Clint值分别为71和214 μL/min/mg，而HLM和CyLM在催化M1和M2形成方面活性较低，Clint值均低于20 μL/min/mg。研究表明，UGT1A1、1A3、1A9、2B7、2B15以及肝外的UGT1A8和1A10参与了GA的葡萄糖醛酸化作用。除UGT1A1外，几乎所有的UGT都更倾向于形成M2。值得注意的是，UGT1A8表现出最高的活性，其Clint值比其他同工型高出5倍以上。使用UGT1A1、1A9、2B7和1A8的选择性抑制剂进行的化学抑制研究进一步表明，UGT1A8对人体肠道GA的葡萄糖醛酸化作用有显著贡献。总之，这项体外研究证明了肝脏和肠道微粒体在GA葡萄糖醛酸化作用方面存在较大的物种差异，并且肠道UGT对人体的这一途径很重要。
