title: Organic anion transporting polypeptide 2B1 is a high-affinity transporter for atorvastatin and is expressed in the human heart.
abstract: BACKGROUND
  The cardiac effects of statins are subject to controversial discussion, and the mechanism of their uptake into the human heart is unknown. A candidate protein is the organic anion transporting polypeptide (OATP) 2B1 (SLCO2B1), because related transporters are involved in the uptake of statins into the human liver. In this study we examine OATP2B1 expression in the human heart and describe statins as inhibitors and substrates of OATP2B1.
  
  
  METHODS
  The expression of OATP2B1 was analyzed in 46 human atrial and 15 ventricular samples, including samples from hearts with dilated cardiomyopathy and hearts with ischemic cardiomyopathy.
  
  
  RESULTS
  Significant messenger ribonucleic acid expression was found in all samples, with no difference in the diseased hearts. However, patients who had taken atorvastatin exhibit decreased OATP2B1 messenger ribonucleic acid expression compared with patients with no statin treatment. OATP2B1 protein was detected at approximately 85 kd in atrial samples, as well as ventricular samples, and could be localized to the vascular endothelium. Furthermore, estrone-3-sulfate transport into OATP2B1-overexpressing Madin-Darby canine kidney II cells was inhibited by various drugs, including atorvastatin, simvastatin, cerivastatin, glyburide (INN, glibenclamide), and gemfibrozil, with the most pronounced effect being found for atorvastatin (inhibition constant, 0.7 +/- 0.4 micromol/L). Whereas simvastatin (lactone) itself was not transported by OATP2B1, atorvastatin was identified as a high-affinity substrate for OATP2B1 (Michaelis-Menten constant, 0.2 micromol/L) by direct transport measurement via liquid chromatography-tandem mass spectrometry.
  
  
  CONCLUSIONS
  OATP2B1 is a high-affinity uptake transporter for atorvastatin and is expressed in the vascular endothelium of the human heart, suggesting its involvement in cardiac uptake of atorvastatin.
authors.affiliation: Research Center of Pharmacology and Experimental Therapeutics and Department of Pharmacology, Ernst Moritz Arndt University, Greifswald, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Grube
authors.forename: Kathleen
authors.initials: K
authors.lastname: Köck
authors.forename: Stefan
authors.initials: S
authors.lastname: Oswald
authors.forename: Katrin
authors.initials: K
authors.lastname: Draber
authors.forename: Konrad
authors.initials: K
authors.lastname: Meissner
authors.forename: Lothar
authors.initials: L
authors.lastname: Eckel
authors.forename: Michael
authors.initials: M
authors.lastname: Böhm
authors.forename: Stephan B
authors.initials: SB
authors.lastname: Felix
authors.forename: Silke
authors.initials: S
authors.lastname: Vogelgesang
authors.forename: Gabriele
authors.initials: G
authors.lastname: Jedlitschky
authors.forename: Werner
authors.initials: W
authors.lastname: Siegmund
authors.forename: Rolf
authors.initials: R
authors.lastname: Warzok
authors.forename: Heyo K
authors.initials: HK
authors.lastname: Kroemer
mesh_terms: D000368:Aged; D000818:Animals; D000924:Anticholesteremic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D000069059:Atorvastatin; D001692:Biological Transport; D004285:Dogs; D004970:Estrone / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors; D005260:Female; D006321:Heart / Q000187:drug effects*; D006538:Heptanoic Acids / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D027361:Organic Anion Transporters / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D011758:Pyrroles / Q000493:pharmacokinetics / Q000494:pharmacology*; D012335:RNA, Ribosomal / Q000302:isolation & purification; D014162:Transfection
chemical_list: D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D027361:Organic Anion Transporters; D011758:Pyrroles; D012335:RNA, Ribosomal; C450859:SLCO2B1 protein, human; D004970:Estrone; D000069059:Atorvastatin; C017296:estrone sulfate