title: Genetics is a major determinant of expression of the human hepatic uptake transporter OATP1B1, but not of OATP1B3 and OATP2B1.
abstract: BACKGROUND
  Organic anion transporting polypeptide (OATP) 1B1, OATP1B3, and OATP2B1 (encoded by SLCO1B1, SLCO1B3, SLCO2B1) mediate the hepatic uptake of endogenous compounds like bile acids and of drugs, for example, the lipid-lowering atorvastatin, thereby influencing hepatobiliary elimination. Here we systematically elucidated the contribution of SLCO variants on expression of the three hepatic OATPs under consideration of additional important covariates.
  
  
  METHODS
  Expression was quantified by RT-PCR and immunoblotting in 143 Caucasian liver samples. A total of 109 rare and common variants in the SLCO1B3-SLCO1B1 genomic region and the SLCO2B1 gene were genotyped by MALDI-TOF mass spectrometry and genome-wide SNP microarray technology. SLCO1B1 haplotypes affecting hepatic OATP1B1 expression were associated with pharmacokinetic data of the OATP1B1 substrate atorvastatin (n = 82).
  
  
  RESULTS
  Expression of OATP1B1, OATP1B3, and OATP2B1 at the mRNA and protein levels showed marked interindividual variability. All three OATPs were expressed in a coordinated fashion. By a multivariate regression analysis adjusted for non-genetic and transcription covariates, increased OATP1B1 expression was associated with the coding SLCO1B1 variant c.388A > G (rs2306283) even after correction for multiple testing (P = 0.00034). This held true for haplotypes harboring c.388A > G but not the functional variant c.521T > C (rs4149056) associated with statin-related myopathy. c.388A > G also significantly affected atorvastatin pharmacokinetics. SLCO variants and non-genetic and regulatory covariates together accounted for 59% of variability of OATP1B1 expression.
  
  
  CONCLUSIONS
  Our results show that expression of OATP1B1, but not of OATP1B3 and OATP2B1, is significantly affected by genetic variants. The SLCO1B1 variant c.388A > G is the major determinant with additional consequences on atorvastatin plasma levels.
authors: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376 Stuttgart, Germany, and University of Tübingen.
authors: Anne T
authors: AT
authors: Nies
authors: Department of Clinical Pharmacology, University of Helsinki and HUSLAB Helsinki University Central Hospital, FI-00014 Helsinki, Finland.
authors: Mikko
authors: M
authors: Niemi
authors: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376 Stuttgart, Germany, and University of Tübingen.
authors: Oliver
authors: O
authors: Burk
authors: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376 Stuttgart, Germany, and University of Tübingen.
authors: Stefan
authors: S
authors: Winter
authors: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376 Stuttgart, Germany, and University of Tübingen.
authors: Ulrich M
authors: UM
authors: Zanger
authors: Division of Clinical Pharmacology and Toxicology, University Hospital Zürich, Rämistrasse 100, 8091 Zürich, Switzerland.
authors: Bruno
authors: B
authors: Stieger
authors: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376 Stuttgart, Germany, and University of Tübingen ; Department of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Tübingen, Otfried-Müller-Strasse 45, 72076 Tübingen, Germany.
authors: Matthias
authors: M
authors: Schwab
authors: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376 Stuttgart, Germany, and University of Tübingen.
authors: Elke
authors: E
authors: Schaeffeler