Laboratory of Metabolomics and Drug-Induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
Academician Workstation, Jiangxi University of Chinese Medicine, Nanchang 330004, China.
Molecules. 2021 Oct 29;26(21):6558. doi: 10.3390/molecules26216558.
C-prenyl coumarins (C-PYCs) are compounds with similar structures and various bioactivities, which are widely distributed in medicinal plants. Until now, the metabolic characterizations of C-PYCs and the relationship between metabolism and bioactivities remain unclear. In this study, ultra-performance chromatography electrospray ionization quadrupole time-of-flight mass spectrometry-based metabolomics (UPLC-ESI-QTOF-MS) was firstly used to determine the metabolic characterizations of three C-PYCs, including meranzin hydrate (MH), isomeranzin (ISM), and meranzin (MER). In total, 52 metabolites were identified, and all of them were found to be novel metabolites. Among these metabolites, 10 were from MH, 22 were from ISM, and 20 were from MER. The major metabolic pathways of these C-PYCs were hydroxylation, dehydrogenation, demethylation, and conjugation with cysteine, -acetylcysteine, and glucuronide. The metabolic rate of MH was much lower than ISM and MER, which was only 27.1% in MLM and 8.7% in HLM, respectively. Additionally, recombinant cytochrome P450 (CYP) screening showed that CYP1A1, 2B6, 3A4, and 3A5 were the major metabolic enzymes involved in the formation of metabolites. Further bioactivity assays indicated that all of these three C-PYCs exhibited anti-inflammatory activity, but the effects of ISM and MER were slightly higher than MH, accompanied by a significant decrease in inflammatory cytokines transcription induced by lipopolysaccharide (LPS) in macrophages RAW 264.7. Taken together, the metabolic characterizations of the three C-PYCs suggested that the side chain of the prenyl group may impact the metabolism and biological activity of C-PYCs.
C-prenyl 香豆素（C-PYCs）是具有相似结构和多种生物活性的化合物，广泛分布于药用植物中。到目前为止，C-PYCs 的代谢特征以及代谢与生物活性之间的关系尚不清楚。在本研究中，首次采用超高效色谱电喷雾电离四极杆飞行时间质谱联用代谢组学（UPLC-ESI-QTOF-MS）来确定三种 C-PYCs（包括水合梅拉宁、异梅拉宁和梅拉宁）的代谢特征。共鉴定出 52 种代谢产物，均为新代谢产物。其中，10 种来自 MH，22 种来自 ISM，20 种来自 MER。这些 C-PYCs 的主要代谢途径为羟化、脱氢、去甲基化以及与半胱氨酸、-乙酰半胱氨酸和葡萄糖醛酸结合。MH 的代谢速率远低于 ISM 和 MER，在 MLM 中的代谢速率仅为 27.1%，在 HLM 中的代谢速率仅为 8.7%。此外，重组细胞色素 P450（CYP）筛选表明 CYP1A1、2B6、3A4 和 3A5 是参与代谢物形成的主要代谢酶。进一步的生物活性测定表明，这三种 C-PYCs 均具有抗炎活性，但 ISM 和 MER 的效果略高于 MH，同时伴随着 LPS 诱导的巨噬细胞 RAW264.7 中炎症细胞因子转录显著减少。综上所述，三种 C-PYCs 的代谢特征表明，侧链的异戊烯基可能影响 C-PYCs 的代谢和生物活性。
