Genetics is a major determinant of expression of the human hepatic uptake transporter OATP1B1, but not of OATP1B3 and OATP2B1.

Anne T Nies,Mikko Niemi,Oliver Burk,Matthias Schwab,Bruno Stieger,Elke Schaeffeler,Ulrich M Zanger,Stefan Winter

doi:10.1186/gm405

Abstract

BackgroundOrganic 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.MethodsExpression 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).ResultsExpression 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.ConclusionsOur 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.

Highlights

Organic anion transporting polypeptide (OATP) 1B1, OATP1B3, and OATP2B1 mediate the hepatic uptake of endogenous compounds like bile acids and of drugs, for example, the lipid-lowering atorvastatin, thereby influencing hepatobiliary elimination
The transcription factors hepatocyte nuclear factor (HNF)1a, farnesoid X receptor (FXR), liver X receptor (LXR)a, specificity protein 1 (Sp1), aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), and HNF3b were selected because literature data indicate they are involved in regulation of the three hepatic SLCO genes with potential consequences on variability of expression [14,15,16,17,18,19,20,21]
Hepatic OATP expression OATP1B1, OATP1B3, and OATP2B1 mRNA and protein expression varied considerably within the 143 liver samples and were not normally distributed (Figure 1; Figure S2 in Additional file 1). mRNA and protein expression weakly correlated for SLCO1B1/OATP1B1 and SLCO1B3/ OATP1B3, but not for SLCO2B1/OATP2B1 (Figure 1b-d)

Summary

Introduction

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. The organic anion transporting polypeptides 1B1 (OATP1B1, encoded by the SLCO1B1 gene), OATP1B3 (SLCO1B3), and OATP2B1 (SLCO2B1) are major uptake transporters on the sinusoidal membrane of human hepatocytes They mediate the influx of endogenous compounds such as bile salts, bilirubin glucuronides, thyroid hormones and steroid hormone metabolites, and clinically frequently used drugs like statins, HIV protease inhibitors, Numerous clinical studies support the relevance of common and rare SLCO1B1 missense variants altering either the pharmacokinetics or drug response of OATP1B1 substrates [4,7,8]. SLCO variants and non-genetic and regulatory covariates accounted for 59% of variability of hepatic OATP1B1 expression

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