Division of Clinical Pharmacology, University of Stellenbosch, Cape Town, South Africa.
Division of Medical Microbiology, University of Stellenbosch, Cape Town, South Africa; Synexa Life Sciences, Montague Gardens, Cape Town, South Africa.
J Ethnopharmacol. 2021 Apr 24;270:113766. doi: 10.1016/j.jep.2020.113766. Epub 2021 Jan 1.
Withania somnifera (L.) Dunal (Solanaceae) is a traditional herb, used in African indigenous systems of medicine for the treatment of various diseases (including HIV/AIDS and tuberculosis). The relevance of clinically significant interactions of Withania with ARVs and anti-TB drugs needs to be investigated.
This study evaluated the effects of its roots on cytochromes P450 (CYPs) 2B6, 3A4, and rifampicin metabolism pathway, using methanol, ethanol, aqueous, and ethyl acetate solvent extractions.
The extracts were tested on human liver microsomes (HLM) for CYP inhibition, mRNA expression in HepG2 cells for CYP induction. Biochemical qualitative tests and LC-MS/MS methodology were used to determine active phytoconstituents.
The methanolic and ethyl acetate extracts inhibited CYP2B6 with ICs 79.16 and 57.96 μg/ml respectively, while none of the extracts had any effect on rifampicin metabolism or showed time-dependant inhibition (TDI). All extracts were moderate inducers of CYP3A4; the aqueous extract exhibited 38%-fold shift induction of CYP3A4 compared to the control. The methanolic extract had the lowest CTC (50% of cytotoxicity inhibition) (67.13 ± 0.83 μg/ml). LC-MS/MS-PDA full scans were consistent with the presence of flavone salvigenin (m/z 327), alkaloid isopelletierine (m/z 133), steroidal lactone 2,3-dihydrowithaferin-A (m/z 472), and other withanolides including withaperuvin I (m/z 533), withaferin derivative (m/z 567), some of these compounds likely being responsible for the observed CYP2B6 inhibition and CYP3A4 induction. The putative gastrointestinal tract (GIT) concentration for the active extracts was 1800 μg/ml and the hepatic circulation concentrations were estimated at about 220 μg/ml and 13.5 μg/ml for the methanolic and ethyl acetate extracts, respectively. The extrapolated in vivo percentage of inhibition was at 85% for the methanolic extract against CYP2B6.
The findings reported in this study suggest that W. somnifera extracts have the potential of causing clinically significant herb-drug interactions (HDI) as moderate inducer of CYP3A4 and inhibitor of CYP2B6 metabolism pathway (methanol and ethyl acetate extracts).
睡茄（Withania somnifera（L.）Dunal）（茄科）是一种传统草药，在非洲本土医学体系中用于治疗各种疾病（包括 HIV/AIDS 和结核病）。需要研究与 ARV 和抗结核药物的临床显著相互作用的睡茄相关性。
本研究评估了其根对细胞色素 P450（CYP）2B6、3A4 和利福平代谢途径的影响，使用甲醇、乙醇、水和乙酸乙酯溶剂提取物。
将提取物用人肝微粒体（HML）进行 CYP 抑制试验，在 HepG2 细胞中进行 CYP 诱导的 mRNA 表达试验。使用生化定性试验和 LC-MS/MS 方法学来确定活性植物成分。
甲醇和乙酸乙酯提取物分别以 ICs79.16 和 57.96μg/ml 抑制 CYP2B6，而没有一种提取物对利福平代谢有任何影响，也没有表现出时间依赖性抑制（TDI）。所有提取物均为 CYP3A4 的中度诱导剂；与对照相比，水提取物对 CYP3A4 的诱导作用达到 38 倍。甲醇提取物的 CTC（细胞毒性抑制的 50%）最低（67.13±0.83μg/ml）。LC-MS/MS-PDA 全扫描结果与黄酮 salvigenin（m/z327）、生物碱异pelletierine（m/z133）、甾体内酯 2,3-二氢 withaferin-A（m/z472）以及包括 withaperuvin I（m/z533）、withaferin 衍生物（m/z567）在内的其他 withanolides 的存在一致，这些化合物可能是观察到的 CYP2B6 抑制和 CYP3A4 诱导的原因。活性提取物的假定胃肠道（GIT）浓度为 1800μg/ml，甲醇和乙酸乙酯提取物的肝循环浓度估计分别约为 220μg/ml 和 13.5μg/ml。甲醇提取物对 CYP2B6 的体内抑制百分比为 85%。
本研究报告的结果表明，睡茄提取物具有引起临床显著草药-药物相互作用（HDI）的潜力，作为 CYP3A4 的中度诱导剂和 CYP2B6 代谢途径的抑制剂（甲醇和乙酸乙酯提取物）。
