OCTN1

OCTN1 (organic cation / carnitine transporter 1)

Aliases: DFNB60, ergothioneine transporter (ETT)
Gene name:  Solute carrier family 22 member 4 (SLC22A4)

Summary

OCTN1 is a widely expressed organic cation transporter. Alongside OCTN2, it plays a role in L-carnitine tissue distribution and renal reabsorption, although ergothionene appears to be a preferred endogenous substrate. It is polyspecific, and appears to act as both a Na⁺-dependent and Na⁺-independent uptake transporter, or exchanger of organic cations, zwitterions, and protons. It is implicated in Crohn’s disease, the renal secretion of gabapentin, CNS penetration of oxaliplatin, as well as in the disposition of cationic respiratory medicines in the lung. As there is very limited information on the clinical relevance of OCTN1 to drug ADME or DDI, it is not currently included in the FDA or EMA guidances.

Localization

OCTN1 is widely expressed in human tissues [1-3]. It also appears to have higher mRNA expression than OCTN2 in many tissues. It is located on the brush-border membrane (urine side) of proximal tubule cells and on the luminal (air) side of airway epithelial cells [4, 5]. An interesting site of strong expression is the CD14+ monocyte [6, 7]. There are reports of OCTN1 localisation in mitochondria, as well as significant species differences in both localization and transport mechanism between human and rat; in particular, high hepatic expression in the rat that is absent in human [8]. Its function in mitochondria requires further investigation, but may be important for carnitine accumulation in this organelle. 

Function, physiology, and clinically significant polymorphisms

OCTN1 was first cloned from a human fetal liver cDNA library [4-6]. OCTN1 has 11 predicted transmembrane domains, and can variously function as an organic cation/proton exchanger, a cation exchanger, or a Na⁺-dependent or Na⁺-independent zwitterion transporter. The function of OCTN1 has been shown to depend on direct interaction with cholesterol, as the removal of cholesterol from native OCTN1 before reconstitution in proteoliposomes resulted in impaired transport activity [9]. The physiological substrates are carnitine, an important component in the transport of fatty acids to the mitochondria, and the antioxidant amino acid ergothioneine, with ergothioneine being a superior substrate [10]. In the kidney, OCTN1 participates in the active secretion and reabsorption of small organic cations and zwitterions, such as carnitine and ergothioneine. OCTN1 may be important in the reabsorption of zwitterions and the secretion of cations in the proximal tubule. The antiepileptic gabapentin is a clinical substrate of OCTN1; patients with a point mutation leading to reduced uptake of gabapentin have reduced renal secretion of this drug [11-13]. As OCTN1 is expressed in the apical membrane, it is possible that OCTN1 contributes to the apical transport of gabapentin in the intestine and kidney [12]. OCTN2, and to a lesser extent OCTN1, transports some important respiratory medicines (ipratropium and tiotropium), and due to its expression in the lung it may influence the disposition and absorption of these medicines in the lung [14, 15]. Both OCTN1 and 2 are involved in the renal disposition as well as tubular reabsorption of the hepatitis B drug entecavir [16]. OCTN1 also transports the tyrosine kinase inhibitor saracatinib, a therapeutic drug used to treat rheumatoid arthritis [17]. The transport activity of OCTN1 can be inhibited by quinidine, verapamil, pyrilamine, spermine, choline, γ-butyrobetaine and ipratropium [14, 18, 19]. 
Genetic polymorphisms of OCTN1 and OCTN2 have been linked to Crohn’s diseases and colorectal cancer [20-22]. Variants of the SLC22A4 gene are also associated with susceptibility to rheumatoid arthritis [11]. The common variant L503F is capable of much higher metformin uptake than wild-type OCTN1, while the I306T variant transports gabapentin less efficiently [23]. 

Clinical significance

Ergothioneine, a food-derived sulfur-containing amino acid, is a major natural substrate of OCTN1, and it exerts antioxidant functions by scavenging radicals. Hence, transport of ergothioneine by OCTN1 protects cells against oxidative damage and has been shown to mitigate chemically induced fibrotic injury in a mouse model [24]. OCTN1-mediated ergothioneine uptake has been hypothesized to play a more general role in minimizing oxidative damage [25].
Presently there is no direct evidence showing OCTN1 involvement in adverse clinical events; however mechanistic in vitro and in vivo studies suggest a significant role in the disposition of a number of drugs. For example, OCTN1-mediated transport oxaliplatin, more so than that mediated by OCTN2 or OCTs, seems to be an important mechanism contributing to the neuronal accumulation and resulting neurotoxicity of oxaliplatin [26]. The OCTN1 allele rs1050152 is involved in imatinib uptake of chronic myeloid leukemia cells, and it is significantly associated with major molecular response [27]. OCTN1/2 polymorphisms are also relevant to the prognosis of unresectable gastrointestinal stromal tumours treated with imatinib. Time to progression was improved in the presence of the SLC22A4 SNP rs1050152 and the two minor SLC22A5 (OCTN2) alleles rs2631367 and rs2631372 [28]. 

Regulatory requirements

As there is very limited information on the clinical relevance of OCTN1 to drug ADME or DDI, it is not currently included in the FDA or EMA guidances.

References

1.    Garrett, Q., et al., Expression and localization of carnitine/organic cation transporter OCTN1 and OCTN2 in ocular epithelium. Invest Ophthalmol Vis Sci, 2008. 49(11): p. 4844-9.
2.    Kristufek, D., et al., Organic cation transporter mRNA and function in the rat superior cervical ganglion. J Physiol, 2002. 543(Pt 1): p. 117-34.
3.    Wu, X., et al., Functional characteristics and tissue distribution pattern of organic cation transporter 2 (OCTN2), an organic cation/carnitine transporter. J Pharmacol Exp Ther, 1999. 290(3): p. 1482-92.
4.    Koepsell, H. and H. Endou, The SLC22 drug transporter family. Pflugers Arch, 2004. 447(5): p. 666-76.
5.    Tamai, I., et al., Involvement of OCTN1 (SLC22A4) in pH-dependent transport of organic cations. Mol Pharm, 2004. 1(1): p. 57-66.
6.    Tamai, I., et al., Cloning and characterization of a novel human pH-dependent organic cation transporter, OCTN1. FEBS Lett, 1997. 419(1): p. 107-11.
7.    Grundemann, D., The ergothioneine transporter controls and indicates ergothioneine activity--a review. Prev Med, 2012. 54 Suppl: p. S71-4.
8.    Wu, X., et al., Structural and functional characteristics and tissue distribution pattern of rat OCTN1, an organic cation transporter, cloned from placenta. Biochim Biophys Acta, 2000. 1466(1-2): p. 315-27.
9.    Pochini, L., et al., Effect of Cholesterol on the Organic Cation Transporter OCTN1 (SLC22A4). Int J Mol Sci, 2020. 21(3).
10.    Grundemann, D., et al., Discovery of the ergothioneine transporter. Proc Natl Acad Sci U S A, 2005. 102(14): p. 5256-61.
11.    Tokuhiro, S., et al., An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis. Nat Genet, 2003. 35(4): p. 341-8.
12.    Urban, T.J., et al., Effects of genetic variation in the novel organic cation transporter, OCTN1, on the renal clearance of gabapentin. Clin Pharmacol Ther, 2008. 83(3): p. 416-21.
13.    Yamamoto, P.A., et al., Pharmacogenetics-based population pharmacokinetic analysis of gabapentin in patients with chronic pain: Effect of OCT2 and OCTN1 gene polymorphisms. Basic Clin Pharmacol Toxicol, 2019. 124(3): p. 266-272.
14.    Nakamura, T., et al., Transport of ipratropium, an anti-chronic obstructive pulmonary disease drug, is mediated by organic cation/carnitine transporters in human bronchial epithelial cells: implications for carrier-mediated pulmonary absorption. Mol Pharm, 2010. 7(1): p. 187-95.
15.    Mukherjee, M., et al., In-cell Western detection of organic cation transporters in bronchial epithelial cell layers cultured at an air-liquid interface on Transwell inserts. J Pharmacol Toxicol Methods, 2013. 68(2): p. 184-189.
16.    Yang, X., et al., Multiple Drug Transporters Are Involved in Renal Secretion of Entecavir. Antimicrob Agents Chemother, 2016. 60(10): p. 6260-70.
17.    Harrach, S., et al., Importance of the novel organic cation transporter 1 for tyrosine kinase inhibition by saracatinib in rheumatoid arthritis synovial fibroblasts. Sci Rep, 2017. 7(1): p. 1258.
18.    Pochini, L., M. Scalise, and C. Indiveri, Immuno-detection of OCTN1 (SLC22A4) in HeLa cells and characterization of transport function. Int Immunopharmacol, 2015. 29(1): p. 21-6.
19.    Tucker, R.A.J., I.K. Cheah, and B. Halliwell, Specificity of the ergothioneine transporter natively expressed in HeLa cells. Biochem Biophys Res Commun, 2019. 513(1): p. 22-27.
20.    Peltekova, V.D., et al., Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nat Genet, 2004. 36(5): p. 471-5.
21.    Waller, S., et al., Evidence for association of OCTN genes and IBD5 with ulcerative colitis. Gut, 2006. 55(6): p. 809-14.
22.    Martini, M., et al., Association of the OCTN1/1672T variant with increased risk for colorectal cancer in young individuals and ulcerative colitis patients. Inflamm Bowel Dis, 2012. 18(3): p. 439-48.
23.    Futatsugi, A., et al., L503F variant of carnitine/organic cation transporter 1 efficiently transports metformin and other biguanides. J Pharm Pharmacol, 2016. 68(9): p. 1160-9.
24.    Tang, Y., et al., Localization of Xenobiotic Transporter OCTN1/SLC22A4 in Hepatic Stellate Cells and Its Protective Role in Liver Fibrosis. J Pharm Sci, 2016. 105(5): p. 1779-89.
25.    Halliwell, B., I.K. Cheah, and C.L. Drum, Ergothioneine, an adaptive antioxidant for the protection of injured tissues? A hypothesis. Biochem Biophys Res Commun, 2016. 470(2): p. 245-50.
26.    Jong, N.N., et al., Oxaliplatin transport mediated by organic cation/carnitine transporters OCTN1 and OCTN2 in overexpressing human embryonic kidney 293 cells and rat dorsal root ganglion neurons. J Pharmacol Exp Ther, 2011. 338(2): p. 537-47.
27.    Angelini, S., et al., Association between imatinib transporters and metabolizing enzymes genotype and response in newly diagnosed chronic myeloid leukemia patients receiving imatinib therapy. Haematologica, 2013. 98(2): p. 193-200.
28.    Angelini, S., et al., Polymorphisms in OCTN1 and OCTN2 transporters genes are associated with prolonged time to progression in unresectable gastrointestinal stromal tumours treated with imatinib therapy. Pharmacol Res, 2013. 68(1): p. 1-6.
29.    Pochini, L., et al., OCTN: A Small Transporter Subfamily with Great Relevance to Human Pathophysiology, Drug Discovery, and Diagnostics. SLAS Discov, 2019. 24(2): p. 89-110.
30.    Drug Transporters in Drug Disposition, Effects and Toxicity. Advances in Experimental Medicine and Biology. 2019, Singapore: Springer.
31.    Pochini, L., et al., Acetylcholine and acetylcarnitine transport in peritoneum: Role of the SLC22A4 (OCTN1) transporter. Biochim Biophys Acta, 2016. 1858(4): p. 653-60.