Identification and characterization of naturally occurring inhibitors against UDP-glucuronosyltransferase 1A1 in Fructus Psoraleae (Bu-gu-zhi).
As an edible traditional Chinese herb, Fructus psoraleae (FP) has been widely used in Asia for the treatment of vitiligo, bone fracture and osteoporosis. Several cases on markedly elevated bilirubin and acute liver injury following administration of FP and its related proprietary medicine have been reported, but the mechanism in FP-associated toxicity has not been well investigated yet. This study aimed to investigate the inhibitory effects of FP extract and its major constituents against human UDP-glucuronosyltransferase 1A1 (UGT1A1), the key enzyme responsible for metabolic elimination of bilirubin. To this end, N-(3-carboxy propyl)-4-hydroxy-1,8-naphthalimide (NCHN), a newly developed specific fluorescent probe for UGT1A1, was used to evaluate the inhibitory effects of FP extract or its fractions in human liver microsomes (HLM), while LC-UV fingerprint and UGT1A1 inhibition profile were combined to identity and characterize the naturally occurring inhibitors of UGT1A1 in FP. Our results demonstrated that both the extract of FP and five major components of FP displayed evident inhibitory effects on UGT1A1 in HLM. Among these five identified naturally occurring inhibitors, bavachin and corylifol A were found to be strong inhibitors of UGT1A1 with the inhibition kinetic parameters (Ki) values lower than 1 μM, while neobavaisoflavone, isobavachalcone, and bavachinin displayed moderate inhibitory effects against UGT1A1 in HLM, with the Ki values ranging from 1.61 to 9.86μM. These findings suggested that FP contains natural compounds with potent inhibitory effects against human UGT1A1, which may be one of the important reasons for triggering FP-associated toxicity, including elevated bilirubin levels and liver injury.
Liaoning Medical University, Jinzhou, Liaoning, China; Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
Xin-Xin
XX
Wang
Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
Xia
X
Lv
Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
Shi-Yang
SY
Li
Dalian Medical University, Dalian 116044, China.
Jie
J
Hou
Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; Dalian Medical University, Dalian 116044, China.
Jing
J
Ning
Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
Jia-Yue
JY
Wang
Liaoning Medical University, Jinzhou, Liaoning, China; Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
Yun-Feng
YF
Cao
Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China. Electronic address: geguangbo@dicp.ac.cn.
Guang-Bo
GB
Ge
Liaoning Medical University, Jinzhou, Liaoning, China. Electronic address: jyguobin@126.com.
Bin
B
Guo
Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, China.
Ling
L
Yang
D001663:Bilirubin / Q000378:metabolism; D047188:Chalcones / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D047309:Flavones / Q000633:toxicity; D005419:Flavonoids / Q000633:toxicity; D005638:Fruit / Q000737:chemistry; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007529:Isoflavones / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010936:Plant Extracts / Q000633:toxicity*; D029907:Psoralea / Q000737:chemistry*; D000099148:UGT1A1 Enzyme
D001663:Bilirubin; D047188:Chalcones; D047309:Flavones; D005419:Flavonoids; D014453:Glucuronosyltransferase; D007529:Isoflavones; D010936:Plant Extracts; D000099148:UGT1A1 Enzyme; C459212:bavachin; C549829:corylifol A; C549830:neobavaisoflavone; C468754:isobavachalcone; C468752:bavachinin
Fructus psoraleae; Inhibitory effects; LC-UV fingerprint; NCHN; UDP-glucuronosyltransferase 1A1