title: Interaction of hydroxycinnamic acids and their conjugates with organic anion transporters and ATP-binding cassette transporters.
abstract: METHODS
  Hydroxycinnamic acids are abundant antioxidants in our diet. In humans, hydroxycinnamic acids are metabolized to form sulfates and glucuronides, with the majority recovered in urine.
  
  
  RESULTS
  We assessed the potential roles of organic anion transporters (OATs) and ATP-binding cassette (ABC) transporters in the renal uptake and efflux of hydroxycinnamic acid conjugates. Uptake studies using OAT1 (SLC22A6)-, OAT2 (SLC22A7)-, and OAT3 (SLC22A8)-expressing 293H embryonic kidney cells showed that OAT1 and OAT3, but not OAT2, accepted hydroxycinnamic acid conjugates as substrates. OAT1 and OAT3 mediated the basolateral uptake of hydroxycinnamic acid sulfates and glucuronide conjugates, respectively. Hydroxycinnamic acid sulfates are substrates of OAT4 and were capable of trans-stimulating 5-carboxyfluorescein uptake mediated by OAT4. On the other hand, hydroxycinnamic acid conjugates are not substrates for the ABC transporters, multidrug resistance protein 2 (MRP2/ABCC2) or breast cancer resistance protein (BCRP/ABCG2), demonstrated by the inability to alter ATPase activity. Cis-inhibition studies with OATs and MRPs revealed that hydroxycinnamic acid conjugates have limited impact on the transport of model substrates significantly at physiological concentrations.
  
  
  CONCLUSIONS
  Concerted action of OAT1, OAT3, and OAT4 is involved in the elimination of hydroxycinnamic acid conjugates into urine, whereas MRP2 and breast cancer resistance protein are not involved in the disposition of these conjugates.
authors.affiliation: School of Food Science and Nutrition, University of Leeds, Leeds, UK.
authors.forename: Chi C
authors.initials: CC
authors.lastname: Wong
authors.forename: Denis
authors.initials: D
authors.lastname: Barron
authors.forename: Caroline
authors.initials: C
authors.lastname: Orfila
authors.forename: Fabiola
authors.initials: F
authors.lastname: Dionisi
authors.forename: Peter
authors.initials: P
authors.lastname: Krajcsi
authors.forename: Gary
authors.initials: G
authors.lastname: Williamson
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D003373:Coumaric Acids / Q000378:metabolism* / Q000493:pharmacokinetics*; D005452:Fluoresceins / Q000493:pharmacokinetics; D020719:Glucuronides / Q000493:pharmacokinetics; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors / Q000378:metabolism; D013431:Sulfates / Q000493:pharmacokinetics; D010130:p-Aminohippuric Acid / Q000494:pharmacology
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D003373:Coumaric Acids; D005452:Fluoresceins; D020719:Glucuronides; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D027362:Organic Anion Transport Protein 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D013431:Sulfates; D010130:p-Aminohippuric Acid; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; C427207:SLC22A11 protein, human; C490280:SLC22A7 protein, human; C114338:organic anion transport protein 3; C045132:4-carboxyfluorescein