Human Transporters

OCT3

OCT3 (organic cation transporter 3)

Aliases: EMT, EMTH
Gene name:  Solute carrier family 22 member 3 (SLC22A3)

Summary

OCT3 is an uptake transporter with widespread tissue distribution. Although it is a polyspecific transporter of mainly cationic molecules, and it is expressed in the liver and the kidney, it is not considered as important as OCT1 (liver) and OCT2 (kidney) in the respective tissues.  Nonetheless, OCT3 may be important in oral absorption, neurotransmitter reuptake in the brain, acetylcholine release during extraneuronal cholinergic regulations, as well as regulation of histamine release from basophils.  Its widespread tissue distribution indicates it is a potential mediator of drug tissue distribution, and it does appear to have some importance in cardiac tissue drug exposure.
Due to its function as a transporter of drugs and of endogenous neurotransmitters, as well as its genetic polymorphisms and transcriptional regulation, OCT3 involvement in human diseases of the heart, prostate, and liver, as well as in the development of compulsive disorders may ultimately prove to be of more interest than a specific role in DDIs or drug ADME.  
Although OCT2 and OCTs investigations are recommended in the current FDA and EMA guidances, OCT3 remains a low priority transporter for drug ADME and DDI.

Localization

OCT3 has a very broad tissue expression pattern, and its orientation is also tissue-specific. Amongst many other tissues, OCT3 is expressed in neurons, glial cells, and epithelial cells of the choroid plexus [1, 2]. In humans, the highest OCT3 mRNA levels are found in the kidney, liver, placenta, heart, and skeletal muscle. OCT3 is also detected, to a lesser extent, in other organs including the lung and brain, as well as in cancer-derived cell lines [3-6].  OCT3 is localized at the basolateral membrane of trophoblasts in the placenta [5], the sinusoidal membrane of hepatocytes, the basolateral membrane of renal proximal tubule epithelial cells, as well as the luminal membranes of bronchial epithelial cells and small intestinal enterocytes [1, 7]. OCT3 is localized at both the basolateral (blood-facing) and apical (saliva-facing) membranes of salivary gland acinar cells, suggesting a dual role of this transporter in mediating both uptake and efflux of organic cations in the salivary glands [8]. In rodents, OCT3 is found in various areas of the brain including the hippocampus, hypothalamus, and the ependyma of the third ventricle [9, 10].

Function, physiology, and clinically significant polymorphisms

OCT3 is a polyspecific, bi-directional, facilitative diffusional transporter.  The driving force is believed to be the electrochemical gradient of the transported compounds. It has 12 predicted membrane spanning domains. OCT3 transports a wide range of monoamine neurotransmitters, hormones, and steroids [6].  Its broad substrate profile is overlapping with those of OCT1, OCT2, as well as MATE1 and MATE2-K.  Although it is expressed in both the kidney and the liver, it is regarded as a less important contributor to uptake than OCT1 in the liver or OCT2 in the kidney. Because of the dominance of the other OCTs in these tissues, OCT3 has traditionally received relatively scant attention [11, 12]. More recently, however, reduced metformin bioavailability and attenuated pharmacological response to the drug have been detected in Oct3 knockout mice, and a 3’-UTR variant of OCT3 was found associated with reduced metformin response in humans, too, suggesting that OCT3 may significantly contribute to metformin disposition [13].
Since OCT3 mediates transepithelial passage of organic cations into the saliva, OCT3-driven transport of substrate drugs may account for a range of side effects, from taste disturbance often experienced by metformin users to more severe toxic damage resulting in xerostomia and oral mucositis [8, 14].
In the small intestine, absorption of cationic drugs and xenobiotics from the intestinal lumen may be mediated by OCT3 and/or OCTN1-2 in the brush-border membrane [15]. In rodents, studies suggest that OCT3 contributes to serotonin uptake in the brain and might play a role in the modulation of behavior and motor activity [16, 17]. Studies on Oct3 knockout mice suggest that OCT3 might be involved in the regulation of salt uptake, and highlight that OCT3 is the most important organic cationic transporter in the heart [17, 18].
Recent findings have shown that the tyrosine kinase inhibitors imatinib, nilotinib, gefitinib, and erlotinib exert selective and potent inhibitory effects on OCT3. Comparison of the IC50 values to the unbound Cmax of these drugs suggests that potential clinically significant drug-drug interactions might take place between specific tyrosine kinase inhibitors and other drugs that are substrates of OCT3 [19]. Furthermore, cimetidine, a substrate of OCT3, reduces the renal clearance of procainamide [20], ranitidine [21], dofetilide [22], and varenicline [23]. However, as of now there is no direct evidence of drug-drug interactions involving OCT3.
Five non-synonymous single nucleotide polymorphisms (SNPs) have been identified in the SLC22A3 gene. The mutations caused by three of these polymorphisms (A116S, T400I, and A439V) have been shown to decrease the uptake of both 3H-histamine and 3H-MPP+ in transfected cells [24]. OCT3 polymorphisms may also contribute to inter-individual variations in cationic drug disposition. Comparison of SNPs in the SLC22A3 gene in 213 individuals with methamphetamine use disorder and 443 healthy controls suggested a correlation between some of these SNPs and methamphetamine dependence [25].
OCT3 is emerging as a significant component of CNS-related toxicologies and conditions [26-28].  It is also thought to be important in the progression of prostate and hepatocellular cancers, and suspected to be involved in the development of heart failure [29-32].

Clinical significance

Although a promiscuous transporter of cationic drugs, OCT3 is not generally considered a significant mediator of DDI.  Its role in the tissue distribution of drugs is only beginning to be appreciated.  It may be that OCT3 involvement in human diseases of the heart, prostate, and liver, as well as in the development of compulsive disorders may prove to be of more interest than a specific role in DDIs per se.
Interestingly, SLC22A3 was first identified as a coronary artery disease risk locus in a genome-wide association study [33], and the impact of SNPs on cardiovascular health is emerging. The common 3’-UTR variant rs3088442 is associated with lowered coronary heart disease risk. This SNP inhibits OCT3 expression by recruiting a negative regulator miRNA. The resulting OCT3 deficiency attenuates inflammatory response, which is thought to account for its cardiovascular protective effect [34]. Likewise, the SNPs rs2048327, rs1810126, and rs1810126 were associated with a decreased risk of coronary artery disease in the male Han Chinese population [35].

Regulatory requirements

Although OCT2 and OCTs investigations are recommended in the current FDA and EMA guidances, OCT3 remains a low priority transporter for drug ADME and DDI.

Location Endogenous substrates In vitro substrates used experimentally Substrate drugs Inhibitors
basolateral membrane of trophoblasts in the placenta, hepatocyte sinusoidal membrane, basolateral membrane of renal proximal tubule cells, small intestinal enterocytes, neurons

metabolites:
creatinine, L-carnitine, choline, guanidine

neurotransmitters: acetylcholine, dopamine, norepinephrine, epinephrine, serotonin, histamine

hormones:
corticosterone, progesterone, testosterone, agmatine

1-methyl-4-phenylpyridinium (MPP),
tetraethylammonium (TEA),
N-methylnicotinamide

atropine, phenoxybenzamine, prazosin, diphenylhydramine, metformin, cimetidine,
ranitidine, amantadine, ketamine, memantine, phencyclidine, nicotine, clonidine, etilefrine, O-methylisoprenaline dizocilpine, verapamil, procainamide, citalopram, desipramine, imipramine, granisetron, tropisetron, quinine, mitoxantrone, D-amphetamine

decynium22, disprocynium24, O-methylisoprenaline, cimetidine, quinidine, rifampicin, prazosin, phenoxybenzamine, corticosterone, progesterone, β-estradiol

 

References

1.    Muller, J., et al., Drug specificity and intestinal membrane localization of human organic cation transporters (OCT). Biochem Pharmacol, 2005. 70(12): p. 1851-60.
2.    Inazu, M., H. Takeda, and T. Matsumiya, Expression and functional characterization of the extraneuronal monoamine transporter in normal human astrocytes. J Neurochem, 2003. 84(1): p. 43-52.
3.    Grundemann, D., et al., Molecular identification of the corticosterone-sensitive extraneuronal catecholamine transporter. Nat Neurosci, 1998. 1(5): p. 349-51.
4.    Hayer-Zillgen, M., M. Bruss, and H. Bonisch, Expression and pharmacological profile of the human organic cation transporters hOCT1, hOCT2 and hOCT3. Br J Pharmacol, 2002. 136(6): p. 829-36.
5.    Sata, R., et al., Functional analysis of organic cation transporter 3 expressed in human placenta. J Pharmacol Exp Ther, 2005. 315(2): p. 888-95.
6.    Wu, X., et al., Identity of the organic cation transporter OCT3 as the extraneuronal monoamine transporter (uptake2) and evidence for the expression of the transporter in the brain. J Biol Chem, 1998. 273(49): p. 32776-86.
7.    Lips, K.S., et al., Polyspecific cation transporters mediate luminal release of acetylcholine from bronchial epithelium. Am J Respir Cell Mol Biol, 2005. 33(1): p. 79-88.
8.    Lee, N., et al., Taste of a pill: organic cation transporter-3 (OCT3) mediates metformin accumulation and secretion in salivary glands. J Biol Chem, 2014. 289(39): p. 27055-64.
9.    Schmitt, A., et al., Organic cation transporter capable of transporting serotonin is up-regulated in serotonin transporter-deficient mice. J Neurosci Res, 2003. 71(5): p. 701-9.
10.    Gasser, P.J., C.A. Lowry, and M. Orchinik, Corticosterone-sensitive monoamine transport in the rat dorsomedial hypothalamus: potential role for organic cation transporter 3 in stress-induced modulation of monoaminergic neurotransmission. J Neurosci, 2006. 26(34): p. 8758-66.
11.    Motohashi, H., et al., Gene expression levels and immunolocalization of organic ion transporters in the human kidney. J Am Soc Nephrol, 2002. 13(4): p. 866-74.
12.    Koepsell, H., Polyspecific organic cation transporters: their functions and interactions with drugs. Trends Pharmacol Sci, 2004. 25(7): p. 375-81.
13.    Chen, E.C., et al., Targeted disruption of organic cation transporter 3 attenuates the pharmacologic response to metformin. Mol Pharmacol, 2015. 88(1): p. 75-83.
14.    Wagner, D.J., T. Hu, and J. Wang, Polyspecific organic cation transporters and their impact on drug intracellular levels and pharmacodynamics. Pharmacol Res, 2016. 111: p. 237-46.
15.    Koepsell, H. and H. Endou, The SLC22 drug transporter family. Pflugers Arch, 2004. 447(5): p. 666-76.
16.    Kitaichi, K., et al., Behavioral changes following antisense oligonucleotide-induced reduction of organic cation transporter-3 in mice. Neurosci Lett, 2005. 382(1-2): p. 195-200.
17.    Feng, N., et al., Local inhibition of organic cation transporters increases extracellular serotonin in the medial hypothalamus. Brain Res, 2005. 1063(1): p. 69-76.
18.    Zwart, R., et al., Impaired activity of the extraneuronal monoamine transporter system known as uptake-2 in Orct3/Slc22a3-deficient mice. Mol Cell Biol, 2001. 21(13): p. 4188-96.
19.    Minematsu, T. and K.M. Giacomini, Interactions of tyrosine kinase inhibitors with organic cation transporters and multidrug and toxic compound extrusion proteins. Mol Cancer Ther, 2011. 10(3): p. 531-9.
20.    Somogyi, A., A. McLean, and B. Heinzow, Cimetidine-procainamide pharmacokinetic interaction in man: evidence of competition for tubular secretion of basic drugs. Eur J Clin Pharmacol, 1983. 25(3): p. 339-45.
21.    van Crugten, J., et al., Selectivity of the cimetidine-induced alterations in the renal handling of organic substrates in humans. Studies with anionic, cationic and zwitterionic drugs. J Pharmacol Exp Ther, 1986. 236(2): p. 481-7.
22.    Abel, S., et al., Effect of cimetidine and ranitidine on pharmacokinetics and pharmacodynamics of a single dose of dofetilide. Br J Clin Pharmacol, 2000. 49(1): p. 64-71.
23.    Feng, B., et al., Effect of human renal cationic transporter inhibition on the pharmacokinetics of varenicline, a new therapy for smoking cessation: an in vitro-in vivo study. Clin Pharmacol Ther, 2008. 83(4): p. 567-76.
24.    Sakata, T., et al., Functional analysis of human organic cation transporter OCT3 (SLC22A3) polymorphisms. J Pharmacol Sci, 2010. 113(3): p. 263-6.
25.    Aoyama, N., et al., Association between gene polymorphisms of SLC22A3 and methamphetamine use disorder. Alcohol Clin Exp Res, 2006. 30(10): p. 1644-9.
26.    Tachikawa, M. and K. Hosoya, Transport characteristics of guanidino compounds at the blood-brain barrier and blood-cerebrospinal fluid barrier: relevance to neural disorders. Fluids Barriers CNS, 2011. 8(1): p. 13.
27.    Rappold, P.M., et al., Paraquat neurotoxicity is mediated by the dopamine transporter and organic cation transporter-3. Proc Natl Acad Sci U S A, 2011. 108(51): p. 20766-71.
28.    Gunther, J., et al., Catecholamine-related gene expression in blood correlates with tic severity in tourette syndrome. Psychiatry Res, 2012. 200(2-3): p. 593-601.
29.    Solbach, T.F., et al., Organic cation transporter 3: expression in failing and nonfailing human heart and functional characterization. J Cardiovasc Pharmacol, 2011. 58(4): p. 409-17.
30.    Koch, W., et al., Two rare variants explain association with acute myocardial infarction in an extended genomic region including the apolipoprotein(A) gene. Ann Hum Genet, 2013. 77(1): p. 47-55.
31.    Heise, M., et al., Downregulation of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) in human hepatocellular carcinoma and their prognostic significance. BMC Cancer, 2012. 12: p. 109.
32.    Chen, L., et al., Genetic and epigenetic regulation of the organic cation transporter 3, SLC22A3. Pharmacogenomics J, 2013. 13(2): p. 110-20.
33.    Tregouet, D.A., et al., Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease. Nat Genet, 2009. 41(3): p. 283-5.
34.    Li, L., et al., A solute carrier family 22 member 3 variant rs3088442 G-->A associated with coronary heart disease inhibits lipopolysaccharide-induced inflammatory response. J Biol Chem, 2015. 290(9): p. 5328-40.
35.    Zhao, Q., et al., PHACTR1 and SLC22A3 gene polymorphisms are associated with reduced coronary artery disease risk in the male Chinese Han population. Oncotarget, 2017. 8(1): p. 658-663.

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