Expression of the organic anion transporters OATP1B1, OATP1B3, and OATP2B1 in human liver is affected by genetic and nongenetic factors

Transport proteins in the sinusoidal membrane of hepatocytes mediate drug uptake, which is required for hepatic drug metabolism and elimination. Anionic drugs (e.g. statins, methotrexate, digoxin, paclitaxel) may be taken up into the hepatocytes by members of the organic anion transporting polypeptide (OATP) family, i.e. OATP1B1 (gene symbol SLCO1B1), OATP1B3 (SLCO1B3), and OATP2B1 (SLCO2B1) [1]. As interindividual variability of hepatic OATP expression may affect drug response, we systematically investigated genetic and nongenetic factors of OATP expression.

Methods: Liver tissue samples from 150 Caucasians together with detailed demographic and clinical data [2] were used for analysis. Quantitative real-time PCR (TaqMan) and immunoblotting of membrane fractions were used to determine mRNA and protein levels, respectively. Genotyping was performed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and genome-wide single-nucleotide polymorphism microarray technology.

Results: SLCO1B1, SLCO1B3, and SLCO2B1 mRNA levels varied 40-, 67-, and 27-fold, respectively. SLCO1B1 mRNA levels were higher than those of SLCO1B3 and SLCO2B1. OATP1B1, OATP1B3, and OATP2B1 protein levels varied 41-, 87-, and 21-fold, respectively. SLCO1B1 and SLCO1B3 mRNA levels significantly correlated with the respective protein levels. OATP1B1 protein levels correlated with OATP1B3 and OATP2B1 protein levels, and OATP1B3 protein levels with those of OATP2B1. Expression of all 3 hepatic OATPs was lower in liver donors diagnosed as cholestatic than in non-cholestatic ones (univariate analysis). Certain genetic variants affect OATP expression as well.

Conclusion: We identified cholestasis and genetic variants that determine interindividual variability of hepatic OATP expression. These factors may affect hepatic drug elimination of and response to OATP drug substrates (e.g. statins).

Supported by the Robert Bosch Foundation, Stuttgart, Germany, and BMBF grant 03IS2061C

Literature:

1. Nies AT, Schwab M, Keppler D. Interplay of conjugating enzymes with OATP uptake transporters and ABCC/MRP efflux pumps in the elimination of drugs. Expert Opin Drug Metab Toxicol 2008;4:545-5682. Nies AT, Koepsell H, Winter S, Burk O, Klein K, Kerb R, Zanger UM, Keppler D, Schwab M, Schaeffeler E. Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver. Hepatology 2009;50:1227-1240

MALDI-TOF MS - OATP protein - Organic anion transporter - SLCO gene - pharmacogenomics