title: The inhibitory effects of five alkaloids on the substrate transport mediated through human organic anion and cation transporters.
abstract: 1. Human solute carrier transporters (SLCs) are important membrane proteins mediate the cellular transport of many endogenous and exogenous substances. Organic anion/cation transporters (OATs/OCTs) and organic anion transporting polypeptides (OATPs) are essential SLCs involved in drug influx. Drug-drug/herb interactions through competing for specific SLCs often lead to unsatisfied therapeutic outcomes and/or unwanted side effects. In this study, we comprehensively investigated the inhibitory effects of five clinically relevant alkaloids (dendrobine, matrine, oxymatrine, tryptanthrin and chelerythrine) on the substrate transport through several OATs/OCTs and OATPs. 2. We performed transport functional assay and kinetic analysis on the HEK-293 cells over-expressing each SLC gene. 3. Our data showed tryptanthrin significantly inhibited the transport activity of OAT3 (IC50= 0.93 ± 0.22 μM, Ki= 0.43 μM); chelerythrine acted as a potent inhibitor to the substrate transport mediated through OATP1A2 (IC50= 0.63 ± 0.43 μM, Ki= 0.60 μM), OCT1 (IC50= 13.60 ± 2.81 μM) and OCT2 (IC50=10.80 ± 1.16 μM). 4. Our study suggested tryptanthrin and chelerythrine could potently impact on the drug transport via specific OATs/OCTs. Therefore, the co-administration of these alkaloids with drugs could have clinical consequences due to drug-drug/herb interactions. Precautions should be warranted in the multi-drug therapies involving these alkaloids.
authors.affiliation: a Faculty of Pharmacy , The University of Sydney , Sydney , NSW , Australia and.
authors.forename: Tahiatul
authors.initials: T
authors.lastname: Shams
authors.affiliation: a Faculty of Pharmacy , The University of Sydney , Sydney , NSW , Australia and.
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Lu
authors.affiliation: b Save Sight Institute, The University of Sydney , Sydney , NSW , Australia.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhu
authors.affiliation: a Faculty of Pharmacy , The University of Sydney , Sydney , NSW , Australia and.
authors.forename: Fanfan
authors.initials: F
authors.lastname: Zhou
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects*; D004347:Drug Interactions; D057809:HEK293 Cells; D006801:Humans; D027361:Organic Anion Transporters / Q000378:metabolism*; D011807:Quinolizines / Q000494:pharmacology; D000093842:Matrines
chemical_list: D000470:Alkaloids; D027361:Organic Anion Transporters; D011807:Quinolizines; C002077:dendrobine; C037573:oxymatrine; D000093842:Matrines
keywords: Organic anion transporter; organic anion transporting polypeptides; organic cation transporter; solute carrier transporters