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, 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.