title: Characterization of the transport of the bicyclic peptide phalloidin by human hepatic transport proteins.
abstract: Phalloidin, the major phallotoxin of the mushroom Amanita phalloides, enters hepatocytes by a carrier-mediated mechanism. The molecular identity of the transport proteins mediating phalloidin uptake was so far unknown. Earlier studies in rat liver indicated that phalloidin may share a common mechanism of uptake with organic anions like bile salts. In the current study on human transporters, we analyzed the uptake of phalloidin into transfected HEK293 cells stably expressing the recombinant hepatocyte-specific organic anion uptake transporters OATP2 (also termed OATP1B1, OATP-C, LST1, symbol SLC21A6) or OATP8 (OATP1B3 or SLC21A8). Time-dependent uptake of phalloidin was observed with SLC21A6-expressing cells and was inhibited by typical substrates of SLC21A6 such as bromosulfophthalein or cholyltaurine. A K(m) value of 39+/-11 micro M was determined for SLC21A6-mediated phalloidin uptake. Additional inhibitors of phalloidin uptake mediated by SLC21A6 included the immunosuppressive drugs cyclosporin A, FK506, and rapamycin, whereas alpha-amanitin was only a weak inhibitor. Cyclosporin A was a most potent competitive inhibitor for SLC21A6-mediated phalloidin transport with a K(i) value of 51 nM.
authors.affiliation: Division of Tumor Biochemistry, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120, Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fehrenbach
authors.forename: Yunhai
authors.initials: Y
authors.lastname: Cui
authors.forename: Heinz
authors.initials: H
authors.lastname: Faulstich
authors.forename: Dietrich
authors.initials: D
authors.lastname: Keppler
mesh_terms: D000470:Alkaloids / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D027381:Liver-Specific Organic Anion Transporter 1 / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D010590:Phalloidine / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013448:Sulfobromophthalein / Q000494:pharmacology; D016559:Tacrolimus / Q000494:pharmacology; D013656:Taurocholic Acid / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000470:Alkaloids; D002352:Carrier Proteins; D007166:Immunosuppressive Agents; D027381:Liver-Specific Organic Anion Transporter 1; D029362:Organic Anion Transporters, Sodium-Independent; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013448:Sulfobromophthalein; D010590:Phalloidine; C000880:desmethylphalloin; D013656:Taurocholic Acid; D016572:Cyclosporine; D020123:Sirolimus; D016559:Tacrolimus