Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Pharmacology and Toxicology Division, Shanghai Institute of Food and Drug Control, Shanghai, China.
Phytomedicine. 2020 Oct;77:153287. doi: 10.1016/j.phymed.2020.153287. Epub 2020 Jul 21.
Styrax, one of the most famous folk medicines, has been frequently used for the treatment of cardiovascular diseases and skin problems in Asia and Africa. It is unclear whether Styrax or Styrax-related herbal medicines may trigger clinically relevant herb-drug interactions.
This study was carried out to investigate the inhibitory effects of Styrax on human cytochrome P450 enzymes (CYPs) and to clarify whether this herb may modulate the pharmacokinetic behavior of the CYP-substrate drug warfarin when co-administered.
The inhibitory effects of Styrax on CYPs were assayed in human liver microsomes (HLM), while the pharmacokinetic interactions between Styrax and warfarin were investigated in rats. The bioactive constituents in Styrax with strong CYP3A inhibitory activity were identified and their inhibitory mechanisms were carefully investigated.
The inhibitory effects of Styrax on human CYPs were assayed in vitro, while the pharmacokinetic interactions between Styrax and warfarin were studied in rats. Fingerprinting analysis of Styrax coupled with LC-TOF-MS/MS profiling and CYP inhibition assays were used to identify the constituents with strong CYP3A inhibitory activity. The inhibitory mechanism of oleanonic acid (the most potent CYP3A inhibitor occurring in Styrax) against CYP3A4 was investigated by a panel of inhibition kinetics analyses and in silico analysis.
In vitro assays demonstrated that Styrax extract strongly inhibited human CYP3A and moderately inhibited six other tested human CYPs, as well as potently inhibited warfarin 10-hydroxylation in liver microsomes from both humans and rats. In vivo assays demonstrated that compared with warfarin given individually in rats, Styrax (100 mg/kg) significantly prolonged the plasma half-life of warfarin by 2.3-fold and increased the AUC of warfarin by 2.7-fold when this herb was co-administrated with warfarin (2 mg/kg) in rats. Two LC fractions were found with strong CYP3A inhibitory activity and the major constituents in these fractions were characterized by LC-TOF-MS/MS. Five pentacyclic triterpenoid acids (including epibetulinic acid, betulinic acid, betulonic acid, oleanonic acid and maslinic acid) present in Styrax were potent CYP3A inhibitors, and oleanonic acid was a competitive inhibitor against CYP3A-mediated testosterone 6β-hydroxylation.
Styrax and the pentacyclic triterpenoid acids occurring in this herb strongly modulate the pharmacokinetic behavior of warfarin via inhibition of CYP3A.
安息香，一种最著名的民间药物，在亚洲和非洲常被用于治疗心血管疾病和皮肤问题。目前尚不清楚安息香或与安息香相关的草药是否会引起临床相关的药物-药物相互作用。
本研究旨在探讨安息香对人细胞色素 P450 酶（CYPs）的抑制作用，并阐明当与合用的 CYP 底物药物华法林合用时，这种草药是否可能调节华法林的药代动力学行为。
在人肝微粒体（HLM）中测定安息香对 CYP 的抑制作用，同时在大鼠中研究安息香与华法林之间的药代动力学相互作用。鉴定安息香中具有强 CYP3A 抑制活性的生物活性成分，并仔细研究其抑制机制。
体外测定安息香对人 CYP 的抑制作用，同时在大鼠中研究安息香与华法林之间的药代动力学相互作用。采用 LC-TOF-MS/MS 图谱分析结合指纹图谱分析和 CYP 抑制测定，鉴定具有强 CYP3A 抑制活性的成分。通过一系列抑制动力学分析和计算机模拟分析，研究齐墩果酸（安息香中最有效的 CYP3A 抑制剂）对 CYP3A4 的抑制机制。
体外测定表明，安息香提取物强烈抑制人 CYP3A，中度抑制其他六种测试的人 CYP，以及强烈抑制人肝微粒体和大鼠肝微粒体中西法林的 10-羟化。体内测定表明，与单独给予大鼠华法林相比，当这种草药与华法林（2mg/kg）合用时，100mg/kg 的安息香可使华法林的血浆半衰期延长 2.3 倍，并使华法林的 AUC 增加 2.7 倍。发现两种具有强 CYP3A 抑制活性的 LC 馏分，这些馏分中的主要成分通过 LC-TOF-MS/MS 进行了表征。安息香中存在的五种五环三萜酸（包括表桦木酸、桦木酸、桦木酮酸、齐墩果酸和马栗树皮素酸）是强 CYP3A 抑制剂，齐墩果酸是对 CYP3A 介导的睾酮 6β-羟化的竞争性抑制剂。
安息香和这种草药中存在的五环三萜酸通过抑制 CYP3A 强烈调节华法林的药代动力学行为。
