Institute of Interdisciplinary Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Key Laboratory of Biotechnology and Bioresources Utilization, Educational of Minister, College of Life Science, Dalian Minzu University, Dalian 116600, China.
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; Dalian Medical University, Dalian 116044, China.
Chem Biol Interact. 2018 Mar 25;284:48-55. doi: 10.1016/j.cbi.2018.02.009. Epub 2018 Feb 19.
Amentoflavone (AMF), an abundant natural biflavonoid found in many medicinal plants, displays various beneficial effects including anti-inflammatory, anti-oxidative and anti-cancer. Despite the extensive studies on pharmacological activities, the toxicity or undesirable effects of AMF are rarely reported. In this study, the inhibitory effects of AMF on human UDP-glucuronosyltransferases (UGTs) were carefully investigated. AMF displayed strong inhibition towards most of human UGTs including UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4 and 2B17, with the IC values ranging from 0.12 μM to 16.81 μM. Inhibition constants (K) of AMF against various human UGTs varied from 0.29 μM to 11.51 μM. Further investigation demonstrated that AMF was a noncompetitive inhibitor of UGT1A1 mediated NCHN-O-glucuronidation but functioned as a competitive inhibitor of UGT1A1 mediated 4-MU-O-glucuronidation. In addition, AMF was a competitive inhibitor of UGT1A4 mediated TFP-N-glucuronidation in both UGT1A4 and human liver microsomes, while functioned as a competitive inhibitor of UGT1A9 mediated propofol or 4-MU-O-glucuronidation. These findings demonstrated that AMF was a strong and broad-spectrum natural inhibitor of most human UGTs, which might bring potential risks of herb-drug interactions (HDIs) via UGT inhibition. Additionally, this study provided novel insights into the underlying mechanism of AMF-associated toxicity from the perspective of UGT inhibition.
银杏双黄酮（AMF）是一种在许多药用植物中含量丰富的天然二氢黄酮，具有抗炎、抗氧化和抗癌等多种有益作用。尽管对其药理学活性进行了广泛研究，但 AMF 的毒性或不良作用很少有报道。在这项研究中，我们仔细研究了 AMF 对人 UDP-葡糖醛酸基转移酶（UGTs）的抑制作用。AMF 对包括 UGT1A1、1A3、1A4、1A6、1A7、1A8、1A9、1A10、2B4 和 2B17 在内的大多数人 UGTs 显示出强烈的抑制作用，IC 值范围为 0.12 μM 至 16.81 μM。AMF 对各种人 UGTs 的抑制常数（K）从 0.29 μM 到 11.51 μM 不等。进一步的研究表明，AMF 是非竞争性抑制剂，可抑制 UGT1A1 介导的 NCHN-O-葡糖醛酸化，但作为 UGT1A1 介导的 4-MU-O-葡糖醛酸化的竞争性抑制剂。此外，在人肝微粒体和 UGT1A4 中，AMF 是 UGT1A4 介导的 TFP-N-葡糖醛酸化的竞争性抑制剂，而作为 UGT1A9 介导的丙泊酚或 4-MU-O-葡糖醛酸化的竞争性抑制剂。这些发现表明，AMF 是大多数人 UGTs 的一种强而广谱的天然抑制剂，可能通过 UGT 抑制导致草药-药物相互作用（HDIs）的潜在风险。此外，这项研究从 UGT 抑制的角度为 AMF 相关毒性的潜在机制提供了新的见解。
