title: Metabolite profiling analysis of FR429, an ellagitannin purified from Polygonum capitatum, in rat and human liver microsomes, cytosol and rat primary hepatocytes in vitro.
abstract: FR429, an ellagitannin (a type of polyphenol), is isolated and purified from Polygonum capitatum Buch.-Ham.ex D. Don which is the original herbal medicine of the "Re-Lin-Qing" formula used clinically to treat urinary tract infection in China. FR429 has been investigated for its antitumor potential in tumor-bearing nude mice in vivo, but its in vitro anti-tumor effect in hepatoma cell lines was low. Thus, it was of our interest to investigate its metabolism pathways for supporting its in vivo antitumor potential. The metabolic profiles of FR429 were studied in vitro by liquid chromatography coupled to ion trap time-of-flight mass spectrometry. Total eight metabolites were identified in rat and human liver microsomes, cytosol, and rat primary hepatocytes in vitro. Ellagic acid, a reported anti-angiogenic agent, was one of the main metabolites in these biological matrices. Methylated metabolites catalyzed by catechol-O-methyl transferase (COMT) were observed mainly in the in vitro incubation with rat liver cytosol, which was verified by using a COMT specific inhibitor entacapone and supported by molecular docking analysis. Methylated and sulfated metabolites were also found in rat primary hepatocytes in a time-dependent manner. In conclusion, the in vitro metabolism pathways of FR429 were hydrolysis, methylation and sulfation. The anti-tumor effects of its major metabolites should be further studied.
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing 100050, China.
authors.forename: Jing-Yi
authors.initials: JY
authors.lastname: Ma
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.
authors.forename: Xuelin
authors.initials: X
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing 100050, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Fu
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Hu
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.
authors.forename: Penelope M Y
authors.initials: PM
authors.lastname: Or
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing 100050, China.
authors.forename: Ru
authors.initials: R
authors.lastname: Feng
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing 100050, China.
authors.forename: Chi-Yu
authors.initials: CY
authors.lastname: He
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing 100050, China.
authors.forename: Wen-Jing
authors.initials: WJ
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, First Hospital, Jilin University, Changchun 130021, China. Electronic address: tongqian@medmail.com.
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Zhang
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China. Electronic address: yangchaochen@hotmail.com.
authors.forename: Yangchao
authors.initials: Y
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing 100050, China. Electronic address: wangyan@imm.ac.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.
authors.forename: John H K
authors.initials: JH
authors.lastname: Yeung
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D003600:Cytosol / Q000737:chemistry*; D005960:Glucosides / Q000737:chemistry* / Q000494:pharmacology; D022781:Hepatocytes / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D047348:Hydrolyzable Tannins / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D055432:Metabolomics; D051379:Mice; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism*; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D028502:Polygonum / Q000737:chemistry*; D051381:Rats; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D000970:Antineoplastic Agents; C000595462:FR429 compound; D005960:Glucosides; D047348:Hydrolyzable Tannins; C013515:ellagitannin
keywords: Catechol-O-methyl transferase; Ellagitannin; FR429; LC/MS(n)-IT-TOF; Metabolism