OCTN2

OCTN2 (organic cation / carnitine transporter 2)

Aliases: CDSP, carnitine transporter (CTT)
Gene name:  Solute carrier family 22 member 5 (SLC22A5)

Summary

OCTN2 is a widely expressed organic cation transporter. It plays a key role in the oral absorption, tissue distribution, and renal reabsorption of L-carnitine. It is polyspecific, and appears to act as both a Na⁺-dependent and Na⁺-independent uptake transporter of organic cations. It is implicated in systemic carnitine deficiency and in Crohn’s disease, as well as in the disposition of cationic respiratory medicines in the lung. As there is very limited information on the clinical relevance of OCTN2 to drug ADME or DDI, it is not currently included in the FDA or EMA guidances.

Localization

OCTN2 is very widely expressed in human tissues (see Table 5.25). In particular, OCTN2 is expressed on the apical (gut side) of small intestinal enterocytes, the apical brush-border membrane (urine side) of renal proximal renal tubules, and in skeletal muscle, heart, lung, liver and the eye [1, 2].

Function, physiology and clinically significant polymorphisms

OCTN2 has 12 predicted transmembrane domains and is a high affinity, Na⁺-dependent, pH-sensitive co-transporter of L-carnitine primarily responsible for the uptake of L-carnitine into cells. OCTN2 also operates as a polyspecific Na⁺-independent organic cation transporter, and can transport substrates in both directions across the plasma membrane. OCTN2 was first cloned from human kidney and identified as the transporter responsible for systemic carnitine deficiency [3]. OCTN2 has a high degree of sequence homology with OCTN1 [4]. Substrates of OCTN2 include TEA, quinidine, verapamil, pyrilamine, choline, short-chain acyl esters of carnitine, zwitterionic beta-lactam antibiotics, L-lysine and L-methionine [5, 6]. 
OCTN2 mediates the active absoprtion of L-carnitine in the small intestine and its reabsorption in the proximal tubule. OCTN2 also mediates the uptake of L-carnitine into adipocytes, cardiac myocytes, skeletal muscle cells, neurons, brain, lymphocytes, spermatozoa, and across the blood-retinal barrier. L-Carnitine is an essential component in the mitochondrial oxidation of fatty acids. 
In mice containing a missense mutation in Slc22a5, renal excretion of TEA was reduced compared to normal mice, indicating that organic cations are transported in a secretory direction by OCTN2, whereas carnitine is transported in a reabsorptive direction [7].
Alongside with the monocarboxylate transporter MCT1, OCTN2 is considered a promising target for designing prodrugs aimed at aiding oral drug delivery and improving bioavailability [8, 9]. OCTN2 transports some important respiratory drugs (ipratropium and tiotropium), and due to its expression in the lung it may influence the disposition and absorption of these medicines through respiratory epithelia [10, 11]. OCTN1 and 2 are involved in the renal disposition as well as tubular reabsorption of the hepatitis B drug entecavir [12]. OCTN2 mediates the transport of colistin, a last-resort antibiotic used to treat multi-drug resistant Gram-negative bacterial infections including pneumonia [13].
The transport activity of OCTN2 can be inhibited by short-chain and long-chain acyl-carnitines and numerous clinically used drugs. These include anticancer drugs such as imatinib, paclitaxel, vinblastine, and etoposide, as well as the experimental drug cediranib, a vascular endothelial growth factor receptor-2 inhibitor that is in clinical development for the treatment of ovarian, cervical, endometrial, prostate and other tumors [14, 15].
Over 100 polymorphisms of the SLC22A5 gene are known, and some are implicated in primary systemic carnitine defficiency, a recessive disorder of fatty acid oxidation leading to cardiomyopathy, hepatomegaly, and cerebral dysfunction, among other symptoms [16-18]. Polymorphic isoforms of OCTN1 and OCTN2 are also linked to inflammatory bowel diseases [19, 20], although this requires further investigation. 
PPARγ activators, such as rosiglitazone, may up-regulate OCTN2 expression. 

Clinical significance

OCTN2 plays a key role in the absorption, distribution and Na⁺-dependent renal reabsorption of L-carnitine, which is essential for fatty acid metabolism. Polymorphisms affecting function may lead to primary systemic carnitine deficiency (SCD), which is treated by lifetime dietary supplementation with L-carnitine.
The expression of OCTN2 is altered in numerous types of cancer, such as primary glioblastoma and ovarian cancer. In majority of cases, increased expression of OCTN2 is advantageous to the cancer cells, providing them with an alternative energy source for proliferation and growth via increased supply of carnitine required for the β-oxidation [14, 21, 22].
OCTN1/2 polymorphisms are relevant to the prognosis of unresectable gastrointestinal stromal tumors treated with imatinib. Time to progression was improved in the presence of the SLC22A4 (OCTN1) rs1050152 C allele and the two minor alleles (G) in SLC22A5 (OCTN2), rs2631367 and rs2631372 [23]

Regulatory requirements

As there is very limited information on the clinical relevance of OCTN2 to drug ADME or DDI, it is not currently included in the FDA or EMA guidances.

References

1.    Koepsell, H. and H. Endou, The SLC22 drug transporter family. Pflugers Arch, 2004. 447(5): p. 666-76.
2.    Wu, X., et al., cDNA sequence, transport function, and genomic organization of human OCTN2, a new member of the organic cation transporter family. Biochem Biophys Res Commun, 1998. 246(3): p. 589-95.
3.    Tamai, I., et al., Molecular and functional identification of sodium ion-dependent, high affinity human carnitine transporter OCTN2. J Biol Chem, 1998. 273(32): p. 20378-82.
4.    Grigat, S., et al., The carnitine transporter SLC22A5 is not a general drug transporter, but it efficiently translocates mildronate. Drug Metab Dispos, 2009. 37(2): p. 330-7.
5.    Koepsell, H., Polyspecific organic cation transporters: their functions and interactions with drugs. Trends Pharmacol Sci, 2004. 25(7): p. 375-81.
6.    Ohashi, R., et al., Na(+)-dependent carnitine transport by organic cation transporter (OCTN2): its pharmacological and toxicological relevance. J Pharmacol Exp Ther, 1999. 291(2): p. 778-84.
7.    Ohashi, R., et al., Molecular and physiological evidence for multifunctionality of carnitine/organic cation transporter OCTN2. Mol Pharmacol, 2001. 59(2): p. 358-66.
8.    Wang, G., et al., Intestinal OCTN2- and MCT1-targeted drug delivery to improve oral bioavailability. Asian J Pharm Sci, 2020. 15(2): p. 158-173.
9.    Koepsell, H., Organic Cation Transporters in Health and Disease. Pharmacol Rev, 2020. 72(1): p. 253-319.
10.    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.
11.    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.
12.    Yang, X., et al., Multiple Drug Transporters Are Involved in Renal Secretion of Entecavir. Antimicrob Agents Chemother, 2016. 60(10): p. 6260-70.
13.    Visentin, M., et al., Colistin is substrate of the carnitine/organic cation transporter 2 (OCTN2, SLC22A5). Drug Metab Dispos, 2017. 45(12): p. 1240-1244.
14.    Juraszek, B. and K.A. Nalecz, SLC22A5 (OCTN2) Carnitine Transporter-Indispensable for Cell Metabolism, a Jekyll and Hyde of Human Cancer. Molecules, 2019. 25(1).
15.    Hu, C., et al., Inhibition of OCTN2-mediated transport of carnitine by etoposide. 2012. 11(4): p. 921-9.
16.    Nezu, J., et al., Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter. Nat Genet, 1999. 21(1): p. 91-4.
17.    Tang, N.L., et al., Mutations of OCTN2, an organic cation/carnitine transporter, lead to deficient cellular carnitine uptake in primary carnitine deficiency. Hum Mol Genet, 1999. 8(4): p. 655-60.
18.    Wang, Y., et al., Phenotype and genotype variation in primary carnitine deficiency. Genet Med, 2001. 3(6): p. 387-92.
19.    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.
20.    Waller, S., et al., Evidence for association of OCTN genes and IBD5 with ulcerative colitis. Gut, 2006. 55(6): p. 809-14.
21.    Fink, M.A., et al., L-Carnitine-Mediated Tumor Cell Protection and Poor Patient Survival Associated with OCTN2 Overexpression in Glioblastoma Multiforme. Clin Cancer Res, 2019. 25(9): p. 2874-2886.
22.    Elsnerova, K., et al., Gene expression of membrane transporters: Importance for prognosis and progression of ovarian carcinoma. Oncol Rep, 2016. 35(4): p. 2159-70.
23.    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.
24.    Kou, L., et al., Recent advances in drug delivery via the organic cation/carnitine transporter 2 (OCTN2/SLC22A5). Expert Opin Ther Targets, 2018. 22(8): p. 715-726.