Organic anion transporting polypeptide 2B1 is a high-affinity transporter for atorvastatin and is expressed in the human heart.
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.
Grube
Markus
M
Research Center of Pharmacology and Experimental Therapeutics and Department of Pharmacology, Ernst Moritz Arndt University, Greifswald, Germany.
Köck
Kathleen
K
Oswald
Stefan
S
Draber
Katrin
K
Meissner
Konrad
K
Eckel
Lothar
L
Böhm
Michael
M
Felix
Stephan B
SB
Vogelgesang
Silke
S
Jedlitschky
Gabriele
G
Siegmund
Werner
W
Warzok
Rolf
R
Kroemer
Heyo K
HK
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
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