Cho Pil Joung, Paudel Sanjita, Lee Doohyun, Jin Yun Ji, Jo GeunHyung, Jeong Tae Cheon, Lee Sangkyu, Lee Taeho
BK21 Plus KNU Multi-Omics-based Creative Drug Research Team, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea.
College of Pharmacy, Yeungnam University, Gyeongsan 38541, Korea.
Pharmaceutics. 2018 Aug 30;10(3):141. doi: 10.3390/pharmaceutics10030141.
Osthenol is a prenylated coumarin isolated from the root of and , and is an -demethylated metabolite of osthole in vivo. Its various pharmacological effects have been reported previously. The metabolic pathway of osthenol was partially confirmed in rat osthole studies, and 11 metabolic products were identified in rat urine. However, the metabolic pathway of osthenol in human liver microsomes (HLM) has not been reported. In this study, we elucidated the structure of generated metabolites using a high-resolution quadrupole-orbitrap mass spectrometer (HR-MS/MS) and characterized the major human cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) isozymes involved in osthenol metabolism in human liver microsomes (HLMs). We identified seven metabolites (M1-M7) in HLMs after incubation in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) and uridine 5'-diphosphoglucuronic acid (UDPGA). As a result, we demonstrated that osthenol is metabolized to five mono-hydroxyl metabolites (M1-M5) by CYP2D6, 1A2, and 3A4, respectively, a 7-glucuronide conjugate (M6) by UGT1A9, and a hydroxyl-glucuronide (M7) from M5 by UGT1A3 in HLMs. We also found that glucuronidation is the dominant metabolic pathway of osthenol in HLMs.
蛇床子素是从蛇床和毛当归根中分离得到的一种异戊烯基香豆素，是蛇床子素在体内的去甲基化代谢产物。其多种药理作用此前已有报道。在大鼠蛇床子素研究中部分证实了蛇床子素的代谢途径，并在大鼠尿液中鉴定出11种代谢产物。然而，蛇床子素在人肝微粒体（HLM）中的代谢途径尚未见报道。在本研究中，我们使用高分辨率四极杆-轨道阱质谱仪（HR-MS/MS）阐明了生成的代谢产物的结构，并对参与人肝微粒体（HLMs）中蛇床子素代谢的主要人细胞色素P450（CYP）和尿苷5'-二磷酸葡萄糖醛酸转移酶（UGT）同工酶进行了表征。在烟酰胺腺嘌呤二核苷酸磷酸（NADPH）和尿苷5'-二磷酸葡萄糖醛酸（UDPGA）存在下孵育后，我们在HLMs中鉴定出7种代谢产物（M1-M7）。结果表明，在HLMs中，蛇床子素分别被CYP2D6、1A2和3A4代谢为5种单羟基代谢产物（M1-M5），被UGT1A9代谢为一种7-葡萄糖醛酸共轭物（M6），被UGT1A3从M5代谢为一种羟基葡萄糖醛酸（M7）。我们还发现葡萄糖醛酸化是HLMs中蛇床子素的主要代谢途径。
