Alternative titles; symbols
HGNC Approved Gene Symbol: SLC22A1
Cytogenetic location: 6q25.3 Genomic coordinates (GRCh38): 6:160,121,815-160,158,718 (from NCBI)
Polyspecific organic cation transporters in the liver, kidney, and intestine are critical for elimination of many endogenous amines as well as a wide array of drugs and environmental toxins. Grundemann et al. (1994) isolated a cDNA from rat kidney, which they named OCT1 (organic cation transporter), that induced organic cation uptake when expressed in Xenopus oocytes. On Northern blots, rat OCT1 was expressed as 3 mRNAs of 1.9, 3.4, and 4.8 kb in kidney, liver, intestine, and colon.
Using PCR of liver cDNA with primers based on the homologous rat gene, Zhang et al. (1997) cloned human OCT1 cDNA. The predicted 554-amino acid human protein has 12 putative transmembrane domains and is 78% identical to rat OCT1 protein. On Northern blots, OCT1 was expressed as a 2-kb mRNA only in liver, although a weaker 2.5-kb mRNA was seen in several other tissues, including kidney. However, no expression was detected in intestine, lung, or pancreas. On SDS-PAGE, Zhang et al. (1997) observed that OCT1 migrated as a 47-kD protein, smaller than its predicted size of 61 kD. However, Zhang et al. (1997) noted that anomalous migration of membrane proteins such as OCT1 is not unusual.
By PCR of kidney cortex cDNA, Gorboulev et al. (1997) cloned human OCT1 and OCT2 (602608) and found that OCT1 predicted a 553-amino acid protein. By RT-PCR they observed that OCT1 was transcribed in all tissues tested, although on Northern blots it was expressed mainly in liver.
Hayer et al. (1999) reported the cloning of 4 human OCT1 isoforms: a long form and 3 short forms. All 4 variants were identified in a human glioma cell line, whereas only 2 isoforms were found in human liver cDNA. The long form represents the full-length OCT1 gene, since the sequence of this clone is more than 99% identical to previously cloned cDNAs. Elucidation of the gene structure of human OCT1 demonstrated that the other isolated isoforms are alternatively spliced variants. When stably expressed in human embryonic kidney cells, only the full-length OCT1 cDNA mediated a transporter function.
Grundemann et al. (1994) performed functional assays which suggested that OCT1 is the main organic cation uptake system in hepatocytes and has common features with organic cation uptake over the basolateral membrane of renal proximal tubules.
Zhang et al. (1997) observed that Xenopus oocytes expressing OCT1 showed increased cation uptake.
Hayer et al. (1999) determined that the OCT1 gene contains 7 exons.
By somatic cell hybrid PCR mapping followed by fluorescence in situ hybridization, Koehler et al. (1997) mapped the SLC22A1 gene to 6q26.
As part of a pharmacogenetics project that sought to identify genes that determine drug response, Leabman et al. (2003) screened for variation in the set of 24 genes encoding membrane transporters. They identified variants by screening an ethnically diverse collection of genomic DNA samples, derived from a total of 494 chromosomes. By combining population-genetic and phylogenetic analyses, they were able to identify amino acid residues and protein domains that may be important for human fitness. A large sample set made it possible for them also to obtain information about rare variants. The 24 membrane transporters with potential roles in drug response were grouped based on transporter family: e.g., OCT1, OCT2 (602608), and OCT3 (604842) belonged to the SLC6 family; CNT1 (606207) and CNT2 (606208) belonged to the SLC28 family. Leabman et al. (2003) identified 680 SNPs, of which 175 were synonymous and 155 caused amino acid changes, and 29 small insertions and deletions. Amino acid diversity in transmembrane domains (TMDs) was significantly lower than in loop domains, suggesting that TMDs have special functional constraints. Leabman et al. (2003) used allele frequency distribution to evaluate different scoring systems for their ability to predict which SNPs affect function. Their underlying assumption was that alleles that are functionally deleterious will be selected against and thus underrepresented at high frequencies and overrepresented at low frequencies. They found that evolutionary conservation of orthologous sequences, as assessed by evolutionarily conserved/evolutionarily unconserved and SIFT (Sorts Intolerant From Tolerant), was the best predictor of allele frequency distribution and hence of function. European Americans were found to have an excess of high frequency alleles in comparison to African Americans, consistent with a historic bottleneck. In addition, African Americans exhibited a much higher frequency of population-specific medium-frequency alleles than did European Americans.
Because OCT1 interacts with a variety of structurally diverse organic cations, including clinically useful drugs as well as toxic substances, it is an important determinant of systemic exposure to many xenobiotics. To understand the genetic basis of extensive interindividual differences in xenobiotic disposition, Shu et al. (2003) functionally characterized 15 protein-altering variants of the human liver organic cation transporter, OCT1, in Xenopus oocytes. All variants that reduced or eliminated function altered evolutionarily conserved amino acid residues. In general, variants with decreased function had amino acid substitutions that resulted in more radical chemical changes (higher Grantham values) and were less evolutionarily favorable (lower BLOSUM62 values) than variants that maintained function. A variant with increased function (OCT1-S14F) changed an amino acid residue such that the human protein matched the consensus of the OCT1 mammalian orthologs. The results indicated that changes at evolutionarily conserved positions of OCT1 are strong predictors of decreased function and suggested that a combination of evolutionary conservation and chemical change might be a stronger predictor of function.
Shu et al. (2007) investigated the role of OCT1 in the therapeutic effects of the drug metformin, which is widely used in the treatment of type 2 diabetes (see 125853) but to which patients show an extremely variable response. In mouse hepatocytes, deletion of Oct1 resulted in a reduction in the effects of metformin on AMPK (see 602739) phosphorylation and gluconeogenesis; in Oct1-deficient mice, the glucose-lowering effects of metformin were completely abolished. Glucose tolerance tests in healthy volunteers showed significantly lower effects of metformin in individuals carrying reduced-function OCT1 polymorphisms, including the common 420del and R61C variants. Shu et al. (2007) concluded that OCT1 is important for metformin therapeutic action and that genetic variation in OCT1 may contribute to variation in response to the drug.
Gorboulev, V., Ulzheimer, J. C., Akhoundova, A., Ulzheimer-Teuber, I., Karbach, U., Quester, S., Baumann, C., Lang, F., Busch, A. E., Koepsell, H. Cloning and characterization of two human polyspecific organic cation transporters. DNA Cell Biol. 16: 871-881, 1997. [PubMed: 9260930] [Full Text: https://doi.org/10.1089/dna.1997.16.871]
Grundemann, D., Gorboulev, V., Gambaryan, S., Veyhl, M., Koepsell, H. Drug excretion mediated by a new prototype of polyspecific transporter. Nature 372: 549-552, 1994. [PubMed: 7990927] [Full Text: https://doi.org/10.1038/372549a0]
Hayer, M., Bonisch, H., Bruss, M. Molecular cloning, functional characterization and genomic organization of four alternatively spliced isoforms of the human organic cation transporter 1 (hOCT1/SLC22A1). Ann. Hum. Genet. 63: 473-482, 1999. [PubMed: 11388889] [Full Text: https://doi.org/10.1017/S0003480099007770]
Koehler, M. R., Wissinger, B., Gorboulev, V., Koepsell, H., Schmid, M. The two human organic cation transporter genes SLC22A1 and SLC22A2 are located on chromosome 6q26. Cytogenet. Cell Genet. 79: 198-200, 1997. [PubMed: 9605850] [Full Text: https://doi.org/10.1159/000134720]
Leabman, M. K., Huang, C. C., DeYoung, J., Carlson, E. J., Taylor, T. R., de la Cruz, M., Johns, S. J., Stryke, D., Kawamoto, M., Urban, T. J., Kroetz, D. L., Ferrin, T. E. Clark, A. G.; Risch, N.; Herskowitz, I.; Giacomini, K. M.; {Pharmacogenetics of Membrane Transporters Investigators}: Natural variation in human membrane transporter genes reveals evolutionary and functional constraints. Proc. Nat. Acad. Sci. 100: 5896-5901, 2003. [PubMed: 12719533] [Full Text: https://doi.org/10.1073/pnas.0730857100]
Shu, Y., Leabman, M. K., Feng, B., Mangravite, L. M., Huang, C. C., Stryke, D., Kawamoto, M., Johns, S. J., DeYoung, J., Carlson, E., Ferrin, T. E., Herskowitz, I., Giacomini, K. M., Pharmacogenetics of Membrane Transporters Investigators. Evolutionary conservation predicts function of variants of the human organic cation transporter, OCT1. Proc. Nat. Acad. Sci. 100: 5902-5907, 2003. [PubMed: 12719534] [Full Text: https://doi.org/10.1073/pnas.0730858100]
Shu, Y., Sheardown, S. A., Brown, C., Owen, R. P., Zhang, S., Castro, R. A., Ianculescu, A. G., Yue, L., Lo, J. C., Burchard, E. G., Brett, C. M., Giacomini, K. M. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J. Clin. Invest. 117: 1422-1431, 2007. [PubMed: 17476361] [Full Text: https://doi.org/10.1172/JCI30558]
Zhang, L., Dresser, M. J., Gray, A. T., Yost, S. C., Terashita, S., Giacomini, K. M. Cloning and functional expression of a human liver organic cation transporter. Molec. Pharm. 51: 913-921, 1997. [PubMed: 9187257] [Full Text: https://doi.org/10.1124/mol.51.6.913]