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 IC50 values ranging from 0.12 mu M to 16.81 mu M. Inhibition constants (K-i) of AMF against various human UGTs varied from 0.29 mu M to 11.51 mu M. 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.
[1]Shanghai Univ Tradit Chinese Med, Inst Interdisciplinary Med, Shanghai 201203, Peoples R China.
[2]Dalian Minzu Univ, Coll Life Sci, Key Lab Biotechnol & Bioresources Utilizat, Dalian 116600, Peoples R China.
[3]Chinese Acad Sci, Dalian Inst Chem Phys, Dalian 116023, Peoples R China.
[4]Dalian Med Univ, Dalian 116044, Peoples R China.
[5]Southern Med Univ, State Key Lab Organ Failure Res, Guangzhou 510515, Guangdong, Peoples R China.
[6]Dalian Jiaotong Univ, Sch Environm & Chem Engn, Dalian 116028, Peoples R China.
(8.0+极速模式)