Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver

Abstract

An important function of hepatocytes is the biotransformation and elimination of various drugs, many of which are organic cations and are taken up by organic cation transporters (OCTs) of the solute carrier family 22 (SLC22). Because interindividual variability of OCT expression may affect response to cationic drugs such as metformin, we systematically investigated genetic and nongenetic factors of OCT1/SLC22A1 and OCT3/SLC22A3 expression in human liver. OCT1 and OCT3 expression (messenger RNA [mRNA], protein) was analyzed in liver tissue samples from 150 Caucasian subjects. Hepatic OCTs were localized by way of immunofluorescence microscopy. Matrixassisted laser desorption/ionization time-of-flight mass spectrometry and genome-wide singlenucleotide polymorphism microarray technology served to genotype 92 variants in the SLC22A1-A3/ OCT1-3 gene cluster. Transport of metformin by recombinant human OCT1 and OCT3 was compared using transfected cells. OCT1 mRNA and protein expression varied 113-and 83-fold, respectively; OCT3 mRNA expression varied 27-fold. OCT1 transcript levels were on average 15-fold higher compared with OCT3. We localized the OCT3 protein to the basolateral hepatocyte membrane and identified metformin as an OCT3 substrate. OCT1 and OCT3 expression are independent of age and sex but were significantly reduced in liver donors diagnosed as cholestatic (P < 0.01). Several haplotypes for OCT1 and OCT3 were identified. Multivariate analysis adjusted for multiple testing showed that only the OCT1-Arg61Cys variant (rs12208357) strongly correlated with decreased OCT1 protein expression (P < 0.0001), and four variants in OCT3 (rs2292334, rs2048327, rs1810126, rs3088442) were associated with reduced OCT3 mRNA levels (P ‫؍‬ 0.03). Conclusion: We identified cholestasis and genetic variants as critical determinants for considerable interindividual variability of hepatic OCT1 and OCT3 expression. This indicates consequences for hepatic elimination of and response to OCT substrates such as metformin.

Metformin, cancer and glucose metabolism

“…Compared with OCT1 and OCT2, OCT3 shows a much broader tissue distribution and it has been proposed to be a new transporter of metformin in skeletal muscle, heart, brain, placenta and liver (Aoki et al 2008. Excluding adrenal gland, OCT3 is weakly expressed in other tissues including liver where the OCT1:OCT3 mRNA ratio reaches 34 (Nies et al 2009). Hepatic uptake of metformin is primarily mediated by OCT1.…”

Organic Cation Transporter Variation and Response to Smoking Cessation Therapies

“…Assessment of genotype completion rates, genotyped or imputed genotypes from nominated or proxy SNPs, linkage disequilibrium, and minor allele frequencies reduced this to six SNPs with genotyped genotype data (Table 2 and Supplementary Table 4). The non-synonymous SLC22A1 SNP, rs12208357 48,49 was genotyped via TaqMan® SNP Genotyping Assay (Table 2 and Supplementary Table 4). Among the expected 12,873 genotypes, the missing genotype rate was 0.05%.…”

Role of Organic Anion-Transporting Polypeptides for Cellular Mesalazine (5-Aminosalicylic Acid) Uptake

“…Uptake transporters such as members of the organic anion-transporting polypeptide family (OATPs) (gene symbol SLCO), which are located in the luminal membrane of enterocytes and in the basolateral membrane of hepatocytes, are well recognized determinants of drug absorption, distribution, and effects (Nies et al, 2009;Fahrmayr et al, 2010). OATPs transport a broad spectrum of endogenous compounds and drugs (Fahrmayr et al, 2010).…”