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

Abstract:

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, e.g. 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 on mRNA and protein level 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, non-genetic, and regulatory covariates, accounted for 59% of variability of OATP1B1 expression. CONCLUSIONS: Our results showed 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.

PubMed ID: 23311897

Projects: A3.4: Linking signalling to metabolic functions, B5: Cell-cell communication influences detoxifying functions in hepatocytes, G1: Clinical Translation to Invasively Characterized Patients, G2: Clinical Translation to Non-Invasive Volunteer Setting, G3: Clinical Translation to Pharmaceutical Drug Development, G4: Whole-Body Detoxification in Mouse Models

Journal: Genome Med
Citation: Genome Med 5(1): 1
Date Published: 11th Jan 2013

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

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