title: Identification of phalloidin uptake systems of rat and human liver.
abstract: To determine whether the liver toxin phalloidin is transported into hepatocytes by one of the known bile salt transporters, we expressed the sodium-dependent Na+/taurocholate cotransporting polypeptide (Ntcp) and several sodium-independent bile salt transporters of the organic anion transporting polypeptide (OATP/SLCO) superfamily in Xenopus laevis oocytes and measured uptake of the radiolabeled phalloidin derivative [3H]demethylphalloin. We found that rat Oatp1b2 (previously called Oatp4 (Slc21a10)) as well as human OATP1B1 (previously called OATP-C (SLC21A6)) and OATP1B3 (previously called OATP8 (SLC21A8)) mediate uptake of [3H]demethylphalloin when expressed in X. laevis oocytes. Transport of increasing [3H]demethylphalloin concentrations was saturable with apparent Km values of 5.7 microM (Oatp1b2), 17 microM (OATP1B1) and 7.5 microM (OATP1B3). All other tested Oatps/OATPs as well as the rat liver Ntcp did not transport [3H]demethylphalloin. Therefore, we conclude that rat Oatp1b2 as well as human OATP1B1 and OATP1B3 are responsible for phalloidin uptake into rat and human hepatocytes.
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology and Toxicology, University Hospital, Ramistr. 100, CH-8091, Zurich, Switzerland.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Meier-Abt
authors.forename: Heinz
authors.initials: H
authors.lastname: Faulstich
authors.forename: Bruno
authors.initials: B
authors.lastname: Hagenbuch
mesh_terms: D000818:Animals; D000838:Anions; D001692:Biological Transport; D004305:Dose-Response Relationship, Drug; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D027361:Organic Anion Transporters / Q000502:physiology; D029362:Organic Anion Transporters, Sodium-Independent / Q000502:physiology; D010455:Peptides / Q000737:chemistry; D010590:Phalloidine / Q000493:pharmacokinetics*; D051381:Rats; D012964:Sodium / Q000737:chemistry / Q000378:metabolism; D013656:Taurocholic Acid / Q000493:pharmacokinetics; D014982:Xenopus laevis
chemical_list: D000838:Anions; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D010455:Peptides; C421102:Slco1a1 protein, rat; D010590:Phalloidine; D013656:Taurocholic Acid; D012964:Sodium