title: Herb-drug interaction prediction based on the high specific inhibition of andrographolide derivatives towards UDP-glucuronosyltransferase (UGT) 2B7.
abstract: Herb-drug interaction strongly limits the clinical application of herbs and drugs, and the inhibition of herbal components towards important drug-metabolizing enzymes (DMEs) has been regarded as one of the most important reasons. The present study aims to investigate the inhibition potential of andrographolide derivatives towards one of the most important phase II DMEs UDP-glucuronosyltransferases (UGTs). Recombinant UGT isoforms (except UGT1A4)-catalyzed 4-methylumbelliferone (4-MU) glucuronidation reaction and UGT1A4-catalyzed trifluoperazine (TFP) glucuronidation were employed to firstly screen the andrographolide derivatives' inhibition potential. High specific inhibition of andrographolide derivatives towards UGT2B7 was observed. The inhibition type and parameters (Ki) were determined for the compounds exhibiting strong inhibition capability towards UGT2B7, and human liver microsome (HLMs)-catalyzed zidovudine (AZT) glucuronidation probe reaction was used to furtherly confirm the inhibition behavior. In combination of inhibition parameters (Ki) and in vivo concentration of andrographolide and dehydroandrographolide, the potential in vivo inhibition magnitude was predicted. Additionally, both the in vitro inhibition data and computational modeling results provide important information for the modification of andrographolide derivatives as selective inhibitors of UGT2B7. Taken together, data obtained from the present study indicated the potential herb-drug interaction between Andrographis paniculata and the drugs mainly undergoing UGT2B7-catalyzed metabolic elimination, and the andrographolide derivatives as potential candidates for the selective inhibitors of UGT2B7.
authors.affiliation: The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China. Electronic address: cmu4h-mhy@126.com.
authors.forename: Hai-Ying
authors.initials: HY
authors.lastname: Ma
authors.affiliation: School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China.
authors.forename: Dong-Xue
authors.initials: DX
authors.lastname: Sun
authors.affiliation: The First Affiliated Hospital of Liaoning Medical University, Jinzhou 121001, China; Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Zhongshan Road, Dalian 116023, China.
authors.forename: Yun-Feng
authors.initials: YF
authors.lastname: Cao
authors.affiliation: Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Zhongshan Road, Dalian 116023, China.
authors.forename: Chun-Zhi
authors.initials: CZ
authors.lastname: Ai
authors.affiliation: Thyroid Surgery, Yantaishan Hospital, Yantai, Shandong, China.
authors.forename: Yan-Qing
authors.initials: YQ
authors.lastname: Qu
authors.affiliation: Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Zhongshan Road, Dalian 116023, China; Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA.
authors.forename: Cui-Min
authors.initials: CM
authors.lastname: Hu
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Changtao
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Academy of Integrative Medicine, Dalian Medical University, Dalian 116044, China.
authors.forename: Pei-Pei
authors.initials: PP
authors.lastname: Dong
authors.affiliation: Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Zhongshan Road, Dalian 116023, China.
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Sun
authors.affiliation: Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Zhongshan Road, Dalian 116023, China.
authors.forename: Mo
authors.initials: M
authors.lastname: Hong
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Naoki
authors.initials: N
authors.lastname: Tanaka
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: The First Affiliated Hospital of Liaoning Medical University, Jinzhou 121001, China; Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Zhongshan Road, Dalian 116023, China; Academy of Integrative Medicine, Dalian Medical University, Dalian 116044, China; College of Pharmacy, Pharmacokinetic and Drug Transport Key Laboratory, Dalian, Medical University, Dalian, China. Electronic address: maxc1978@163.com.
authors.forename: Xiao-Chi
authors.initials: XC
authors.lastname: Ma
authors.affiliation: The First Affiliated Hospital of Liaoning Medical University, Jinzhou 121001, China; Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Zhongshan Road, Dalian 116023, China; Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. Electronic address: zzfang228@gmail.com.
authors.forename: Zhong-Ze
authors.initials: ZZ
authors.lastname: Fang
mesh_terms: D035685:Andrographis; D004224:Diterpenes / Q000737:chemistry / Q000378:metabolism*; D004794:Enzyme Repression / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000187:drug effects / Q000378:metabolism*; D041743:Herb-Drug Interactions; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology
chemical_list: D004224:Diterpenes; C030419:andrographolide; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; C507232:UGT1A5 protein, human
keywords: Adverse effects; Andrographolide derivatives; Herb–drug interaction (HDI); UDP-glucuronosyltransferases (UGTs)