Research Area

Organic Cation Transporter (OCT)

Introduction of OCT

The organic cation transporter (OCT) is an important drug delivery protein with a broad tissue distribution in the body that mediates the metabolic processes of most drugs. At present, the gene sequence, transport mechanism, substrate structure specificity, regulatory mechanism, gene polymorphism andin vivodistribution characteristics of this transporter have been deeply studied. Based on this knowledge, pharmacologists have successfully delivered many drugs at the transporter molecule level and applied them to clinical practice.

The family members of OCT and their structures respectively

Since Grundemannet al. first cloned the first roct1 gene from a cDNA library of rat renal proximal tubular epithelial cells, human, rabbit, and mouse-derivedoct1were cloned one after another. This family is now named SLC22 (solute carrier family) and belongs to the solute transporter superfamily, including Oct1, Oct2 and Oct3. They have a similar structure and contain 12 transmembrane regions, an intracellular N-terminus, a large glycosylated extracellular hydrophilic ring between TM1 and TM2, and a TM6 and TM7, both of which have a high degree of homology. In the amino acid sequence, Oct1 and Oct2 are 70% similar (in which humans, rats, and mice are 68-69% similar, and human and rabbits are 71% similar). These Oct subtypes mediate the electrogenic transport of small molecule organic cations with different molecular structures that share a wide range of specific substrates. These organic cation substrates include type I organic cations, monovalent small molecule cations such as tetraethylamine (TEA), some important clinical drugs such as metformin, procainamide, citalopram, cisplatin, cimetidine, some endogenous compounds such as dopamine, norepinephrine and some toxic substances RHPP+, HPP+, MPP+, etc.

The regulation of OCT and their research status

Based on their substrate properties and tissue distribution, Oct1, Oct2 and Oct3 play an important role in the distribution of bile, renal excretion, and organic cationic drugs as their substrates in the liver, kidney, heart and brain. To explain the physiological function of Octs, the Slc22a1(oct1), Slc22a2(oct2) and Slc22a3(oct3) gene of the mouse were knocked out, and it was observed that Oct1, Oct2 and Oct3-deficient mice had no abnormality in viability and phenotype, but the oct1-knock gene was small. Liver uptake by TEA and metformin was significantly reduced in mice. In the mice in which both oct1 andoct2 genes were knocked out, the secretion of TEA in the kidneys almost disappeared, and the level of TEA in plasma was significantly increased. The accumulation of MPP+ in the heart and placenta was significantly reduced in oct3-deficient mice compared with wild-type mice. The study of these knockout mice further underscores the important role of Octs in drug elimination and tissue distribution in liver and kidney. The regulatory mechanisms of Octs are important because they alter the mRNA levels and protein levels of Octs, which can alter the absorption and excretion of drugs in tissues. Studies have shown that the PKA activator and inhibitor calmodulin (CaM) regulates the activity of Oct1 and Oct2 by modulating the phosphorylation state of Octs. However, Oct1 is not affected by the PKC activator, and Oct2 can be down-regulated by the PKC activator (DOG). Since multiple transmembrane helices and amino acids are involved in the domain of the Octs substrate binding pocket, the binding sites of different substrates are slightly different, and the phosphorylation and dephosphorylation processes induce molecular structures to change in the pocket domain, thereby affecting different substrates respectively. In recent years, it has been reported that the promoter of Oct1 contains two adjacent recognized DNA response elements (DR-2), which are hepatocyte nuclear factor (HNF-4a) and a firefly containing the Oct1 promoter and capable of being activated by HNF-4a. Overexpression of HNF-4a can increase the expression of Oct1 mRNA. Directed mutagenesis at the binding site of the Oct1 promoter region (HNF-4a) can reduce luciferase activity. The regulation of murine Oct1 transcripts has recently been reported. In the mouse Oct1 promoter, the peroxisome proliferator-activated receptor (PPAT) has been identified and can be transactivated by the known PPAT-gamma activator trehalol and ciglitazone. In addition, 16α-cyanopregone can increase the expression levels of Oct1 and Oct2 mRNA in rat primary cultured liver and kidney cells, and then increase the secretion of Oct1 substrate metformin, MPP+ and TEA secretion. In addition, the glucocorticoid receptor ligand dexamethasone was able to reduce Oct1 mRNA expression levels and was restored to normal levels by administration of the glucocorticoid receptor antagonist RU486. At the same time, the decrease in oct1expression caused a decrease in MMP+ uptake of primary cultured hepatocytes in rats. The Oct2 transcript can be activated by a promoter-local element, and human USF-1 can transactivate the promoter of Oct2. Shuet al. reported the regulation of steroid hormone-mediated Oct2 on MDCK cells. Corresponding to this cell line, the expression level of Oct2 in the kidney of male rats was significantly higher than that in female rats, but the expression of Oct2 in the kidney of female rats could be improved by the treatment of testosterone. Further studies have shown that the androgen receptor element (ARES) located in the Oct2 promoter region plays an important role in the testosterone-dependent gene regulation of rat Oct2. The above studies have shown that transcription factors such as HNF-4α, USF-1 or nuclear receptor ligands can regulate Octs expression levels to varying degrees, thereby changing the pharmacokinetics and tissue distribution of organic cationic drugs.


  1. Hosokawa Y, Takahashi H, Inoue A, et al. Oct-3/4 modulates the drug-resistant phenotype of glioblastoma cells through expression of ATP binding cassette transporter G2. Biochimica et biophysica acta. 2015, 1850(6):1197.
  2. Jeong S H, Lee Y J, Cho B I, et al. OCT-1 overexpression is associated with poor prognosis in patients with well-differentiated gastric cancer. Tumour Biol. 2014, 35(6):5501-5509.
  3. Krogh P J, Jensen P, Dahl S M, et al. Expression and Prognostic Value of Oct-4 in Astrocytic Brain Tumors. Plos One. 2016, 11(12)e0169129.
  4. Yang Y, Wang Y, Yin C, et al. Clinical significance of the stem cell gene Oct-4 in cervical cancer. Tumor Biology. 2014, 35(6):5339-5345.
  5. Wang G, Qiu K L, Lu X H, et al. Comparison and interchangeability of macular thickness measured with Cirrus OCT and Stratus OCT in myopic eyes. International Journal of Ophthalmology. 2015, 8(6):1196.

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