Coumarins are a group of natural compounds commonly found in the families of Rutaceae and Umbelliferae. 7-Isopentenyloxycoumarin (ISC), auraptene (AUR), and umbelliprenin (UM) belong to prenyloxycoumarins (PYCs), which link isopentenyl, geranyl, and farnesyl group at C7 position, respectively. The substituent of 7-ethoxycoumarin (ETC) is the ethyl group. In this study, UPLC–ESI–QTOF–MS (ultra-performance liquid chromatography–electrospray ionization–quadrupole time of flight–MS)-based metabolomics was used to evaluate the in vivo and in vitro metabolism of PYCs. Results showed that ETC produced 10 known metabolites, and ISC was transformed into 17 metabolites in vivo and in vitro, which were undescribed compounds. A total of 35 AUR metabolites, including 34 undescribed metabolites were identified, and 21 metabolites were reported for the first time in UM. The results indicated that hydroxylation and N-acetylcysteine conjugation were the common metabolic reactions for PYCs. The metabolic rates of ETC, ISC, AUR and UM were 26%, 36%, 81%, and 38%, respectively, in human liver microsome, while they were 24%, 40%, 80%, and 37%, respectively, in mouse liver microsomes. In addition, recombinant cytochrome P450s (CYPs) screening showed that CYP1A1, 2C19, 3A4, and 3A5 were the major metabolic enzymes involved in the formation of hydroxylation metabolites. Together, these results suggest that the isopentenyl group plays an important role in the metabolism of PYCs.

中文翻译：

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代谢组学揭示异戊烯基在香豆素代谢中的作用

香豆素是芸香科和伞形科中常见的一组天然化合物。7-异戊烯氧基香豆素 (ISC)、金黄素 (AUR) 和伞形肾上腺素 (UM) 属于异戊烯氧基香豆素 (PYCs)，它们分别在 C7 位连接异戊烯基、香叶基和法尼基。7-乙氧基香豆素（ETC）的取代基是乙基。在本研究中，基于 UPLC-ESI-QTOF-MS（超高效液相色谱-电喷雾电离-四极杆飞行时间-MS）的代谢组学用于评估PYCs的体内和体外代谢。结果显示ETC产生10种已知代谢物，ISC在体内外转化为17种代谢物，它们是未描述的化合物。共鉴定出 35 种 AUR 代谢物，包括 34 种未描述的代谢物，其中 21 种代谢物在 UM 中首次报道。结果表明羟基化和N-乙酰半胱氨酸结合是PYCs的常见代谢反应。ETC、ISC、AUR和UM在人肝微粒体中的代谢率分别为26%、36%、81%和38%，而在人肝微粒体中的代谢率分别为24%、40%、80%和37%，在小鼠肝微粒体中。此外，重组细胞色素 P450s (CYPs) 筛选显示 CYP1A1、2C19、3A4 和 3A5 是参与羟基化代谢物形成的主要代谢酶。总之，这些结果表明异戊烯基在 PYCs 的代谢中起重要作用。