从奇迹树（Moringa oleifera）叶子中分离、合成的次生代谢产物及其对 CYP3A4 和 CYP2D6 同工酶的药物相互作用潜力。
Isolation, synthesis, and drug interaction potential of secondary metabolites derived from the leaves of miracle tree (Moringa oleifera) against CYP3A4 and CYP2D6 isozymes.
机构信息
National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS 38677, USA; Division of Pharmacognosy, Department of BioMolecular Sciences, School of Pharmacy, The University of Mississippi, University, MS 38677, USA; Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 4545, Saudi Arabia.
National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS 38677, USA; Division of Pharmacognosy, Department of BioMolecular Sciences, School of Pharmacy, The University of Mississippi, University, MS 38677, USA.
出版信息
Phytomedicine. 2019 Jul;60:153010. doi: 10.1016/j.phymed.2019.153010. Epub 2019 Jul 2.
BACKGROUND
Moringa oleifera Lam. is known as a drumstick tree that is widely cultivated in various subtropical and tropical provinces. Previous studies indicated that both aqueous and methanolic extracts of M. oleifera leaves have potent inhibitory effects on two major drug metabolizing Cytochrome P450 enzymes, namely, CYP3A4 and CYP2D6.
PURPOSE
The current study was aimed to isolate the secondary metabolites from M. oleifera and investigate their cytotoxicity and inhibitory effects on CYP3A4 and CYP2D6 to assess their herb-drug interaction (HDI) potential.
METHODS
Chemical structure elucidation was achieved by interpreting the spectroscopic data (UV, IR, 1D, and 2D NMR experiments), confirming by HR-ESI-MS, and comparing with the previously reported data in the literature. All the isolates were evaluated for their cytotoxicity against a panel of cell lines (SK-MEL, KB, BT-549, SK-OV-3, VERO, LLC-PK1, and HepG2) and inhibition of two principal CYP isozymes (CYP3A4 and CYP2D6).
RESULTS
Phytochemical investigation of M. oleifera leaves resulted in the isolation and characterization of one new compound, namely omoringone (1), along with twelve known secondary metabolites (2-13) belonging to several chemical classes including flavonoids, terpenoids, lignans, and phenylalkanoids. A plausible biosynthetic pathway for compound 1 was provided. Because of the low isolation yield and limited supply, omoringone (1) and niazirin (12) were successively synthesized. No cytotoxicity was observed on any of the tested cell lines up to 50 µM. The extract exhibited an inhibitory effect on CYP3A4 isoform (IC = 52.5 ± 2.5 µg/ml). Among the isolates, 1-4 and 7-9 inhibited CYP3A4 with the IC values ranging from 41.5 to 100 µM with no remarkable effect on CYP2D6 isozyme.
CONCLUSION
This work aided in ascertaining components of M. oleifera contributing to CYP3A4 inhibition exhibited by the extract using an in vitro assay. Nonetheless, further studies are warranted to determine the bioavailability of the phytochemicals and extrapolate these findings in more physiologically relevant conditions to further establish the clinical relevance of in vitro observations.
背景
辣木树又称鼓槌树，广泛种植于亚热带和热带省份。先前的研究表明，辣木叶的水提物和甲醇提取物均对细胞色素 P450 酶（CYP）的两个主要亚型 CYP3A4 和 CYP2D6 具有很强的抑制作用。
目的
本研究旨在从辣木叶中分离出次生代谢产物，并考察其对 CYP3A4 和 CYP2D6 的细胞毒性和抑制作用，以评估其草药-药物相互作用（HDI）的潜力。
方法
通过解析光谱数据（UV、IR、1D 和 2D NMR 实验）、高分辨电喷雾质谱（HR-ESI-MS）确认并与文献中报道的数据进行比较，对化合物的化学结构进行了阐述。对所有分离得到的化合物进行了细胞毒性测试，以评估它们对 SK-MEL、KB、BT-549、SK-OV-3、VERO、LLC-PK1 和 HepG2 细胞系的抑制作用，并对两种主要 CYP 同工酶（CYP3A4 和 CYP2D6）的抑制作用。
结果
对辣木叶的化学成分进行研究，分离并鉴定了一种新化合物，即 omoringone（1），以及 12 种已知的次生代谢产物（2-13），这些化合物属于黄酮类、萜类、木脂素类和苯丙素类等化学类别。提出了化合物 1 的可能生物合成途径。由于分离产率低且供应有限，omoringone（1）和 niazirin（12）被成功合成。在 50µM 时，所有测试的细胞系均未观察到任何细胞毒性。提取物对 CYP3A4 同工酶具有抑制作用（IC50=52.5±2.5µg/ml）。在所分离的化合物中，化合物 1-4 和 7-9 对 CYP3A4 的抑制作用 IC50 值范围为 41.5-100µM，对 CYP2D6 同工酶无明显影响。
结论
本研究采用体外试验，确定了辣木叶提取物中对 CYP3A4 抑制作用的成分。然而，还需要进一步的研究来确定这些化学成分的生物利用度，并在更接近生理条件的情况下推断这些发现，以进一步确定体外观察的临床相关性。
Zotero 插件