title: Proton-Coupled Organic Cation Antiporter Contributes to the Hepatic Uptake of Matrine.
abstract: Matrine is the major bioactive alkaloid found in certain Sophora plants and has been used for the treatment of liver diseases and protection of liver function. The aim of this study was to investigate the human liver uptake mechanism of matrine by using HepG2 cells as the in vitro model. Matrine was transported into HepG2 cells in a time- and temperature-dependent manner. The cellular uptake was saturable and was significantly reduced by the metabolic inhibitors, such as sodium azide and rotenone. Furthermore, the uptake of matrine was found to be regulated by a protonophore (carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone) and pH, indicating that this influx transporter may be a proton-coupled antiporter. The uptake of matrine was sensitive to inhibition by the cationic drugs including pyrilamine, quinidine, verapamil, amantadine, diphenhydramine, and cimetidine but insensitive to other typical substrates or inhibitors of well-known organic cation transport systems. The present study reveals that, for the first time, in HepG2 cells, the existence of a proton-coupled organic cation antiporter that contributes substantially to the hepatic uptake of matrine.
authors.affiliation: Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education (China Pharmaceutical University), Nanjing 210009, China; Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Chunyong
authors.initials: C
authors.lastname: Wu
authors.affiliation: Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education (China Pharmaceutical University), Nanjing 210009, China; Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Sun
authors.affiliation: Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education (China Pharmaceutical University), Nanjing 210009, China; Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Feng
authors.affiliation: Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education (China Pharmaceutical University), Nanjing 210009, China; Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutics of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Hufang
authors.initials: H
authors.lastname: Wang
authors.affiliation: Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education (China Pharmaceutical University), Nanjing 210009, China; Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China. Electronic address: fengfang1@126.com.
authors.forename: Fang
authors.initials: F
authors.lastname: Feng
authors.affiliation: Department of Pharmaceutics of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing 210009, China. Electronic address: ivy366300@hotmail.com.
authors.forename: Junying
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000470:Alkaloids / Q000378:metabolism* / Q000494:pharmacology*; D017920:Antiporters / Q000378:metabolism* / Q000494:pharmacology*; D001692:Biological Transport / Q000502:physiology*; D002412:Cations / Q000494:pharmacology; D045744:Cell Line, Tumor; D056945:Hep G2 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism; D011522:Protons; D011807:Quinolizines / Q000378:metabolism* / Q000494:pharmacology*; D000093842:Matrines
chemical_list: D000470:Alkaloids; D017920:Antiporters; D002412:Cations; D027701:Organic Cation Transport Proteins; D004364:Pharmaceutical Preparations; D011522:Protons; D011807:Quinolizines; D000093842:Matrines
keywords: HepG2 cells; hepatic transport; matrine; proton-coupled organic cation antiporter