The different metabolism of morusin in various species and its potent inhibition against UDP-glucuronosyltransferase (UGT) and cytochrome p450 (CYP450) enzymes |
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| Authors: | Xianbao Shi Shuman Yang Gang Zhang Yonggui Song Dan Su Yali Liu |
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| Institution: | 1. Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, China,;2. Department of Pharmacy, The First Affiliated Hospital of Liaoning Medical University, Jinzhou, China,;3. Department of Internal Medicine/Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada,;4. Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, USA, and;5. National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, China |
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| Abstract: | 1.?The aim of this study was to investigate the inhibitory effect of morusin on Glucuronosyltransferase (UGT) isoforms and cytochrome P450 enzymes (CYP450s). We also investigated the metabolism of morusin in human, rat, dog, monkey, and minipig liver microsomes.2.?100?μM of morusin exhibited strong inhibition on all UGTs and CYP450s. The half inhibition concentration (IC50) values for CYP3A4, CYP1A2, CYP2C9, CYP2E1, UGT1A6, UGT1A7, and UGT1A8 were 2.13, 1.27, 3.18, 9.28, 4.23, 0.98, and 3.00?μM, and the inhibition kinetic parameters (Ki) were 1.34, 1.16, 2.98, 6.23, 4.09, 0.62, and 2.11?μM, respectively.3.?Metabolism of morusin exhibited significant species differences. The quantities of M1 from minipig, monkey, dog, and rat were 7.8, 11.9, 2.0, and 6.3-fold of human levels. The Km values in HLMs, RLMs, MLMs, DLMs, and PLMs were 7.84, 22.77, 14.32, 9.13, and 22.83?μM, and Vmax for these species were 0.09, 1.23, 1.43, 0.15, and 0.75?nmol/min/mg, respectively. CLint (intrinsic clearance) values (Vmax/Km) for morusin obeyed the following order: monkey?>?rat?>?minipig?>?dog?>?human. CLH (hepatic clearance) values for humans, dogs, and rats were calculated to be 8.28, 17.38, and 35.12?mL/min/kg body weight, respectively.4.?This study provided vital information to understand the inhibitory potential and metabolic behavior of morusin among various species. |
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| Keywords: | Cytochrome P450 (CYP450) drug–drug interactions glucuronosyltransferase (UGT) morusin |
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