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Journal articles on the topic 'OCTN2'

Author: Grafiati

Published: 4 June 2021

Last updated: 15 February 2022

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1

Pochini, Lorena, Michele Galluccio, Mariafrancesca Scalise, Lara Console, and Cesare Indiveri. "OCTN: A Small Transporter Subfamily with Great Relevance to Human Pathophysiology, Drug Discovery, and Diagnostics." SLAS DISCOVERY: Advancing the Science of Drug Discovery 24, no. 2 (December 7, 2018): 89–110. http://dx.doi.org/10.1177/2472555218812821.

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OCTN is a small subfamily of membrane transport proteins that belongs to the larger SLC22 family. Two of the three members of the subfamily, namely, OCTN2 and OCTN1, are present in humans. OCTN2 plays a crucial role in the absorption of carnitine from diet and in its distribution to tissues, as demonstrated by the occurrence of severe pathologies caused by malfunctioning or altered expression of this transporter. These findings suggest avoiding a strict vegetarian diet during pregnancy and in childhood. Other roles of OCTN2 are related to the traffic of carnitine derivatives in many tissues. The role of OCTN1 is still unclear, despite the identification of some substrates such as ergothioneine, acetylcholine, and choline. Plausibly, the transporter acts on the control of inflammation and oxidative stress, even though knockout mice do not display phenotypes. A clear role of both transporters has been revealed in drug interaction and delivery. The polyspecificity of the OCTNs is at the base of the interactions with drugs. Interestingly, OCTN2 has been recently exploited in the prodrug approach and in diagnostics. A promising application derives from the localization of OCTN2 in exosomes that represent a noninvasive diagnostic tool.

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2

Pochini, Lorena, Mariafrancesca Scalise, Michele Galluccio, and Cesare Indiveri. "OCTN Cation Transporters in Health and Disease." Journal of Biomolecular Screening 18, no. 8 (June 14, 2013): 851–67. http://dx.doi.org/10.1177/1087057113493006.

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The three members of the organic cation transporter novel subfamily are known to be involved in interactions with xenobiotic compounds. These proteins are characterized by 12 transmembrane segments connected by nine short loops and two large hydrophilic loops. It has been recently pointed out that acetylcholine is a physiological substrate of OCTN1. Its transport could be involved in nonneuronal cholinergic functions. OCTN2 maintains the carnitine homeostasis, resulting from intestinal absorption, distribution to tissues, and renal excretion/reabsorption. OCTN3, identified only in mouse, mediates also carnitine transport. OCTN1 and OCTN2 are associated with several pathologies, such as inflammatory bowel disease, primary carnitine deficiency, diabetes, neurological disorders, and cancer, thus representing useful pharmacological targets. The function and interaction with drugs of OCTNs have been studied in intact cell systems and in proteoliposomes. The latter experimental model enables reduced interference from other transporters or enzyme pathways. Using proteoliposomes, the molecular bases of toxicity of some drugs have recently been revealed. Therefore, proteoliposomes represent a promising experimental tool suitable for large-scale molecular screening of interactions of OCTNs with chemicals regarding human health.

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3

Kobayashi, Daisuke, Ikumi Tamai, Yoshimichi Sai, Kazuhiro Yoshida, Tomohiko Wakayama, Yasuto Kido, Jun-ichi Nezu, Shoichi Iseki, and Akira Tsuji. "Transport of carnitine and acetylcarnitine by carnitine/organic cation transporter (OCTN) 2 and OCTN3 into epididymal spermatozoa." Reproduction 134, no. 5 (November 2007): 651–58. http://dx.doi.org/10.1530/rep-06-0173.

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Carnitine and acetylcarnitine are important for the acquisition of motility and maturation of spermatozoa in the epididymis. In this study, we examined the involvement of carnitine/organic cation transporter (OCTN) in carnitine and acetylcarnitine transport in epididymal spermatozoa of mice. Uptake of both compounds by epididymal spermatozoa was time-dependent and partially Na+-dependent. Kinetic analyses revealed the presence of a high-affinity transport system in the spermatozoa, withKmvalues of 23.6 and 6.57 μM for carnitine and acetylcarnitine respectively in the presence of Na+. Expression of OCTN2 and OCTN3 in epididymal spermatozoa was confirmed by immunofluorescence analysis. The involvement of these two transporters in carnitine and acetylcarnitine transport was supported by a selective inhibition study. We conclude that both Na+-dependent and -independent carnitine transporters, OCTN2 and OCTN3, mediate the supply of carnitine and acetylcarnitine to epididymal spermatozoa in mice.

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4

Burckhardt, Gerhard, and Natascha A. Wolff. "Structure of renal organic anion and cation transporters." American Journal of Physiology-Renal Physiology 278, no. 6 (June 1, 2000): F853—F866. http://dx.doi.org/10.1152/ajprenal.2000.278.6.f853.

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Here we review the structural and functional properties of organic anion transporters (OAT1, OAT2, OAT3) and organic cation transporters (OCTN1, OCTN2, OCT1, OCT2, OCT3), some of which are involved in renal proximal tubular organic anion and cation secretion. These transporters share a predicted 12-transmembrane domain (TMD) structure with a large extracellular loop between TMD1 and TMD2, carrying potential N-glycosylation sites. Conserved amino acid motifs revealed a relationship to the sugar transporter family within the major facilitator superfamily. Following heterologous expression, most OATs transported the model anion p-aminohippurate (PAH). OAT1, but not OAT2, exhibited PAH-α-ketoglutarate exchange. OCT1–3 transported the model cations tetraethylammonium (TEA), N1-methylnicotinamide, and 1-methyl-4-phenylpyridinium. OCTNs exhibited transport of TEA and/or preferably the zwitterionic carnitine. Substrate substitution as well as cis-inhibition experiments demonstrated polyspecificity of the OATs, OCTs, and OCTN1. On the basis of comparison of the structurally closely related OATs and OCTs, it may be possible to delineate the binding sites for organic anions and cations in future experiments.

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5

Koch, Alexander, Bettina König, Sebastian Luci, Gabriele I. Stangl, and Klaus Eder. "Dietary oxidised fat up regulates the expression of organic cation transporters in liver and small intestine and alters carnitine concentrations in liver, muscle and plasma of rats." British Journal of Nutrition 98, no. 5 (November 2007): 882–89. http://dx.doi.org/10.1017/s000711450775691x.

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It has been shown that treatment of rats with clofibrate, a synthetic agonist of PPARα, increases mRNA concentration of organic cation transporters (OCTN)-1 and -2 and concentration of carnitine in the liver. Since oxidised fats have been demonstrated in rats to activate hepatic PPARα, we tested the hypothesis that they also up regulate OCTN. Eighteen rats were orally administered either sunflower-seed oil (control group) or an oxidised fat prepared by heating sunflower-seed oil, for 6 d. Rats administered the oxidised fat had higher mRNA concentrations of typical PPARα target genes such as acyl-CoA oxidase, cytochrome P450 4A1 and carnitine palmitoyltransferases-1A and -2 in liver and small intestine than control rats (P < 0·05). Furthermore, rats treated with oxidised fat had higher hepatic mRNA concentrations of OCTN1 (1·5-fold) and OCTN2 (3·1-fold), a higher carnitine concentration in the liver and lower carnitine concentrations in plasma, gastrocnemius and heart muscle than control rats (P < 0·05). Moreover, rats administered oxidised fat had a higher mRNA concentration of OCTN2 in small intestine (2·4-fold; P < 0·05) than control rats. In conclusion, the present study shows that an oxidised fat causes an up regulation of OCTN in the liver and small intestine. An increased hepatic carnitine concentration in rats treated with the oxidised fat is probably at least in part due to an increased uptake of carnitine into the liver which in turn leads to reduced plasma and muscle carnitine concentrations. The present study supports the hypothesis that nutrients acting as PPARα agonists influence whole-body carnitine homeostasis.

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6

Karimian Pour, Navaz, Eliza R. McColl, and Micheline Piquette-Miller. "Impact of Viral Inflammation on the Expression of Renal Drug Transporters in Pregnant Rats." Pharmaceutics 11, no. 12 (November 22, 2019): 624. http://dx.doi.org/10.3390/pharmaceutics11120624.

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Inflammation impacts the expression and function of drug transporters at term-gestation; however, the impact of inflammation on the expression of drug transporters at mid-gestation is largely unknown. Since renal drug transporters play a key role in the clearance of many drugs prescribed during pregnancy, our objective was to study the impact of the viral mimetic poly I:C on the expression of renal transporters in pregnant rats at mid-gestation. Poly I:C (10 mg/kg) or saline was administered intraperitoneally to pregnant Sprague–Dawley rats on gestational day 14. Expression of renal transporters was measured at 6, 24, and 48 h by qRT-PCR and Western blot. The mRNA levels of Mdr1a, Mrp4, Oct2, Octn1, Octn2, Mate1, Oat1-3, Urat1, Oatp4c1, Ent1, and Pept2 were significantly lower in the poly I:C group at 6 h. At 24 h, only the mRNA levels of Oct2, Oatp4c1, and Ent1 were decreased compared to saline. Poly I:C significantly decreased protein expression of Urat1 at 24 h, and P-gp, Oct2, Mate1, Oat1, Oat3 at 48 h,. Poly I:C imposed significant reductions in the expression of several key renal transporters at mid-gestation in pregnant rats. Thus, viral infection may impact renal excretion of drug transporter substrates, potentially leading to drug–disease interactions.

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7

Srinivas, Sonne R., Puttur D. Prasad, Nagavedi S. Umapathy, Vadivel Ganapathy, and Prem S. Shekhawat. "Transport of butyryl-l-carnitine, a potential prodrug, via the carnitine transporter OCTN2 and the amino acid transporter ATB0,+." American Journal of Physiology-Gastrointestinal and Liver Physiology 293, no. 5 (November 2007): G1046—G1053. http://dx.doi.org/10.1152/ajpgi.00233.2007.

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l-Carnitine is absorbed in the intestinal tract via the carnitine transporter OCTN2 and the amino acid transporter ATB0,+. Loss-of-function mutations in OCTN2 may be associated with inflammatory bowel disease (IBD), suggesting a role for carnitine in intestinal/colonic health. In contrast, ATB0,+ is upregulated in bowel inflammation. Butyrate, a bacterial fermentation product, is beneficial for prevention/treatment of ulcerative colitis. Butyryl-l-carnitine (BC), a butyrate ester of carnitine, may have potential for treatment of gut inflammation, since BC would supply both butyrate and carnitine. We examined the transport of BC via ATB0,+ to determine if this transporter could serve as a delivery system for BC. We also examined the transport of BC via OCTN2. Studies were done with cloned ATB0,+ and OCTN2 in heterologous expression systems. BC inhibited ATB0,+-mediated glycine transport in mammalian cells (IC50, 4.6 ± 0.7 mM). In Xenopus laevis oocytes expressing human ATB0,+, BC induced Na+-dependent inward currents under voltage-clamp conditions. The currents were saturable with a K0.5 of 1.4 ± 0.1 mM. Na+ activation kinetics of BC-induced currents suggested involvement of two Na+ per transport cycle. BC also inhibited OCTN2-mediated carnitine uptake (IC50, 1.5 ± 0.3 μM). Transport of BC via OCTN2 is electrogenic, as evidenced from BC-induced inward currents. These currents were Na+ dependent and saturable ( K0.5, 0.40 ± 0.02 μM). We conclude that ATB0,+ is a low-affinity/high-capacity transporter for BC, whereas OCTN2 is a high-affinity/low-capacity transporter. ATB0,+ may mediate intestinal absorption of BC when OCTN2 is defective.

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8

Sayed-Ahmed, Mohamed M., Meshan Lafi Aldelemy, Mohamed M. Hafez, and Othman A. Al-Shabanah. "Inhibition of Gene Expression of Organic Cation/Carnitine Transporter and Antioxidant Enzymes in Oxazaphosphorines-Induced Acute Cardiomyopathic Rat Models." Oxidative Medicine and Cellular Longevity 2012 (2012): 1–13. http://dx.doi.org/10.1155/2012/452902.

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It is well documented that high therapeutic doses of oxazaphosphorines, cyclophosphamide (CP) and ifosfamide (IFO), are associated with cardiomyopathy. This study investigated whether oxazaphosphorines alter the expression of organic cation/carnitine transporter (OCTN2) and antioxidant genes and if so, whether these alterations contribute to CP and IFO-induced cardiotoxicity. Adult male Wistar albino rats were assigned to one of six treatment groups namely, control, L carnitine, CP, IFO, CP plus L carnitine and IFO plus L carnitine. In cardiac and kidney tissues, CP and IFO significantly decreased mRNA and protein expression of OCTN2. Oxazaphosphorines significantly increased serum acyl-carnitine/free carnitine ratio and urinary carnitine excretion and significantly decreased total carnitine in cardiac tissues. Interestingly, carnitine supplementation completely reversed the biochemical and gene expression changes-induced by oxazaphosphorines to the control values, except OCTN2 expression remained inhibited by IFO. Data from this study suggest that: (1) Oxazaphosphorines decreased myocardial carnitine content following the inhibition of OCTN2 mRNA and protein expression in cardiac tissues. (2) Oxazaphosphorine therapy increased urinary loss of carnitine secondary to the inhibition of OCTN2 mRNA and protein expression in proximal tubules of the kidney. (3) Carnitine supplementation attenuates CP but not IFO-induced inhibition of OCTN2 mRNA and protein expression in heart and kidney tissues.

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9

Shekhawat, Prem S., Han-Soo Yang, Michael J. Bennett, Alva Lee Carter, Dietrich Matern, Ikumi Tamai, and Vadivel Ganapathy. "Carnitine Content and Expression of Mitochondrial β-Oxidation Enzymes in Placentas of Wild-Type (OCTN2+/+) and OCTN2 Null (OCTN2−/−) Mice." Pediatric Research 56, no. 3 (September 2004): 323–28. http://dx.doi.org/10.1203/01.pdr.0000134252.02876.55.

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10

Elimrani, Ihsan, Karim Lahjouji, Ernest Seidman, Marie-Josée Roy, Grant A. Mitchell, and Ijaz Qureshi. "Expression and localization of organic cation/carnitine transporter OCTN2 in Caco-2 cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 284, no. 5 (May 1, 2003): G863—G871. http://dx.doi.org/10.1152/ajpgi.00220.2002.

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l-Carnitine is derived both from dietary sources and biosynthesis. Dietary carnitine is absorbed in the small intestine and then distributed to other organs. Previous studies using Caco-2 cells demonstrated that the transport ofl-carnitine in the intestine involves a carrier-mediated system. The purpose of this study was to determine whether the uptake of l-carnitine in Caco-2 cells is mediated by the recently identified organic cation/carnitine transporter (OCTN2). Kinetics ofl-[3H]carnitine uptake were investigated with or without specific inhibitors. l-Carnitine uptake in mature cells was sodium dependent and linear with time. K m and Vmax values for saturable uptake were 14.07 ± 1.70 μM and 26.3 ± 0.80 pmol · mg protein−1 · 6 min−1, respectively. l-carnitine uptake was inhibited ( P < 0.05–0.01) by valproate and other organic cations. Anti-OCTN2 antibodies recognized a protein in the brush-border membrane (BBM) of Caco-2 cells with an apparent molecular mass of 60 kDa. The OCTN2 expression was confirmed by double immunostaining. Our results demonstrate that l-carnitine uptake in differentiated Caco-2 cells is primarily mediated by OCTN2, located on the BBM.

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11

YABUUCHI, Hikaru, Rikiya OHASHI, Kazuki SAKAMOTO, Jun-ichi NEZU, Asuka OKU, Miyuki SHIMANE, Yoshimichi SAI, Ikumi TAMAI, and Akira TSUJI. "MOLECULAR AND FUNCTIONAL IDENTIFICATION OF NOVEL HUMAN ORGANIC CATION TRANSPORTER FAMILY, OCTN1 AND OCTN2." Drug Metabolism and Pharmacokinetics 13, supplement (1998): 106–7. http://dx.doi.org/10.2133/dmpk.13.supplement_106.

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12

Xu, S., Q. Garrett, P. Simmons, J. Vehige, and M. Willcox. "Expression and Localization of Carnitine/Organic Cation Transporter OCTN1 and OCTN2 in Ocular Epithelium." Journal of Proteomics & Bioinformatics S2, no. 01 (July 2008): 320–21. http://dx.doi.org/10.4172/jpb.s1000229.

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13

Garrett, Qian, Shunjiang Xu, Peter A. Simmons, Joseph Vehige, Judith L. Flanagan, and Mark D. Willcox. "Expression and Localization of Carnitine/Organic Cation Transporter OCTN1 and OCTN2 in Ocular Epithelium." Investigative Opthalmology & Visual Science 49, no. 11 (November 1, 2008): 4844. http://dx.doi.org/10.1167/iovs.07-1528.

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14

Broderick, Tom L., Adil El Midaoui, Jean-Louis Chiasson, Donghao Wang, Marek Jankowski, and Jolanta Gutkowska. "The effects of exercise training on γ-butyrobetaine hydroxylase and novel organic cation transporter-2 gene expression in the rat." Applied Physiology, Nutrition, and Metabolism 36, no. 6 (December 2011): 781–89. http://dx.doi.org/10.1139/h11-094.

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The concentration of carnitine in plasma is generally increased with exercise training, suggesting that either carnitine biosynthesis is stimulated or renal reabsorption of carnitine is enhanced, or both. Carnitine, an essential cofactor in the oxidation of fatty acids, is released into the plasma following hydroxylation by γ-butyrobetaine hydroxylase (BBH), the final enzyme in the biosynthetic pathway found primarily in the liver. The organic cation transporter (OCTN2), the carnitine transporter found in kidney, is important in the distribution of carnitine by facilitating its renal reabsorption from urine. In this study, we tested the hypothesis that exercise training increases gene and protein expression of BBH and OCTN2, resulting in enhanced plasma carnitine levels. Male Wistar rats were subjected to 2 daily exercise sessions of treadmill running, 5 days per week, for a 10-week period. The concentration of total carnitine in plasma was significantly increased in trained rats compared with sedentary rats. In trained rats, mRNA and protein expression of BBH were increased in liver, whereas only BBH mRNA expression was increased in kidney. Liver of trained rats demonstrated increased mRNA and protein expression of OCTN2 compared with sedentary rats. In kidney of trained rats, however, only an increase in mRNA expression of OCTN2 was observed. Our results suggest that the improved plasma carnitine status in the trained rat is associated with increased carnitine biosynthesis in liver and kidney. The observation that OCTN2 expression was increased in kidney suggests a potential role of the kidney in the reabsorption of carnitine from the urine.

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15

Szabó, Kitti, Zoltán Nagy, Viktória Juhász, Joseph K. Zolnerciks, Attila Csorba, Zoltán Tímár, Éva Molnár, et al. "Species specificity profiling of rat and human organic cation/carnitine transporter Slc22a5/SLC22A5 (Octn2/OCTN2)." Drug Metabolism and Pharmacokinetics 32, no. 3 (June 2017): 165–71. http://dx.doi.org/10.1016/j.dmpk.2016.08.005.

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16

Upadhyay, Aman, Layla Al-Nakkash, and Tom L. Broderick. "Effects of Exercise Training on Renal Carnitine Biosynthesis and Uptake in the High-Fat and High-Sugar-Fed Mouse." Molecules 25, no. 9 (April 30, 2020): 2100. http://dx.doi.org/10.3390/molecules25092100.

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(1) Background: Diet-induced obesity inhibits hepatic carnitine biosynthesis. Herein, the effects of high-fat (HF) and high-sugar (HFHS) feeding and exercise training (ET) on renal carnitine biosynthesis and uptake were determined. (2) Methods: Male C57BL/6J mice were assigned to the following groups: lean control (standard chow), HFHS diet, and HFHS diet with ET. ET consisted of 150 min of treadmill running per week for 12 weeks. Protein levels of γ-butyrobetaine hydroxylase (γ-BBH) and organic cation transporter-2 (OCTN2) were measured as markers of biosynthesis and uptake, respectively. (3) Results: HFHS feeding induced an obese diabetic state with accompanying hypocarnitinemia, reflected by decreased free carnitine levels in plasma and kidney. This hypocarnitinemia was associated with decreased γ-BBH (~30%) and increased OCTN2 levels (~50%). ET failed to improve the obesity and hyperglycemia, but improved insulin levels and prevented the hypocarnitinemia. ET increased protein levels of γ-BBH, whereas levels of OCTN2 were decreased. Peroxisome proliferator-activated receptor-alpha content was not changed by the HFHS diet or ET. (4) Conclusions: Our results indicate that ET prevents the hypocarnitinemia induced by HFHS feeding by increasing carnitine biosynthesis in kidney. Increased expression of OCTN2 with HFHS feeding suggests that renal uptake was stimulated to prevent carnitine loss.

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17

Smeets, Nori J. L., Carlijn H. C. Litjens, Jeroen J. M. W. van den Heuvel, Hedwig van Hove, Petra van den Broek, Frans G. M. Russel, Jan B. Koenderink, and Saskia N. de Wildt. "Completing the Enalaprilat Excretion Pathway—Renal Handling by the Proximal Tubule." Pharmaceutics 12, no. 10 (September 30, 2020): 935. http://dx.doi.org/10.3390/pharmaceutics12100935.

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Background: Enalapril is often used in the treatment of cardiovascular diseases. Clinical data suggest that the urinary excretion of enalaprilat, the active metabolite of enalapril, is mediated by renal transporters. We aimed to identify enalaprilat specificity for renal proximal tubular transporters. Methods: Baculovirus-transduced HEK293 cells overexpressing proximal tubular transporters were used to study enalaprilat cellular uptake. Uptake into cells overexpressing the basolateral transporters OCT2, OAT1, OAT2, or OAT3 and apical transporters OAT4, PEPT1, PEPT2, OCTN1, OCTN2, MATE1, MATE2k, and URAT1 was compared with mock-transduced control cells. Transport by renal efflux transporters MRP2, MPR4, P-gp, and BCRP was tested using a vesicular assay. Enalaprilat concentrations were measured using LC-MS/MS. Results: Uptake of enalaprilat into cells expressing OAT3 as well as OAT4 was significantly higher compared to control cells. The enalaprilat affinity for OAT3 was 640 (95% CI: 520–770) µM. For OAT4, no reliable affinity constant could be determined using concentrations up to 3 mM. No transport was observed for other transporters. Conclusion: The affinity of enalaprilat for OAT3 and OAT4 was notably low compared to other substrates. Taking this affinity and clinically relevant plasma concentrations of enalaprilat and other OAT3 substrates into account, we believe that drug–drug interactions on a transporter level do not have a therapeutic consequence and will not require dose adjustments of enalaprilat itself or other OAT3 substrates.

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18

Gazouli, Maria. "Single nucleotide polymorphisms of OCTN1, OCTN2, and DLG5 genes in Greek patients with Crohn’s disease." World Journal of Gastroenterology 11, no. 47 (2005): 7525. http://dx.doi.org/10.3748/wjg.v11.i47.7525.

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19

Kobayashi, Daisuke, Masanori Irokawa, Tomoji Maeda, Akira Tsuji, and Ikumi Tamai. "Carnitine/organic cation transporter OCTN2-mediated transport of carnitine in primary-cultured epididymal epithelial cells." Reproduction 130, no. 6 (December 2005): 931–37. http://dx.doi.org/10.1530/rep.1.00737.

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Carnitine is essential for the acquisition of motility and maturation of spermatozoa in the epididymis, and is accumulated in epididymal fluid. In this study, carnitine transport into primary-cultured rat epididymal epithelial cells was characterized to clarify the nature of the transporter molecules involved. Uptake of carnitine by primary-cultured epididymal epithelial cells was time, Na+and concentration dependent. Kinetic analysis of carnitine uptake by the cells revealed the involvement of high- and low-affinity transport systems withKm values of 21 μM and 2.2 mM respectively. The uptake of carnitine by the cells was significantly reduced by inhibitors of carnitine/organic cation transporter (OCTN2), such as carnitine analogues and cationic compounds. In RT-PCR analysis, OCTN2 expression was detected. These results demonstrated that the high-affinity carnitine transporter OCTN2, which is localized at the basolateral membrane of epididymal epithelial cells, mediates carnitine supply into those cells from the systemic circulation as the first step of permeation from blood to spermatozoa.

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20

Salomon, Johanna J., Julia C. Gausterer, Mohammed Ali Selo, Ken-ichi Hosoya, Hanno Huwer, Nicole Schneider-Daum, Claus-Michael Lehr, and Carsten Ehrhardt. "OCTN2-Mediated Acetyl-l-Carnitine Transport in Human Pulmonary Epithelial Cells In Vitro." Pharmaceutics 11, no. 8 (August 7, 2019): 396. http://dx.doi.org/10.3390/pharmaceutics11080396.

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The carnitine transporter OCTN2 is associated with asthma and other inflammatory diseases. The aims of this work were (i) to determine carnitine uptake into freshly isolated human alveolar type I (ATI)-like epithelial cells in primary culture, (ii) to compare the kinetics of carnitine uptake between respiratory epithelial in vitro cell models, and (iii) to establish whether any cell line was a suitable model for studies of carnitine transport at the air-blood barrier. Levels of time-dependent [3H]-acetyl-l-carnitine uptake were similar in ATI-like, NCl-H441, and Calu-3 epithelial cells, whereas uptake into A549 cells was ~5 times higher. Uptake inhibition was more pronounced by OCTN2 modulators, such as l-Carnitine and verapamil, in ATI-like primary epithelial cells compared to NCl-H441 and Calu-3 epithelial cells. Our findings suggest that OCTN2 is involved in the cellular uptake of acetyl-l-carnitine at the alveolar epithelium and that none of the tested cell lines are optimal surrogates for primary cells.

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21

Lahjouji, Karim, Ihsan Elimrani, Julie Lafond, Line Leduc, Ijaz A. Qureshi, and Grant A. Mitchell. "l-Carnitine transport in human placental brush-border membranes is mediated by the sodium-dependent organic cation transporter OCTN2." American Journal of Physiology-Cell Physiology 287, no. 2 (August 2004): C263—C269. http://dx.doi.org/10.1152/ajpcell.00333.2003.

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Maternofetal transport of l-carnitine, a molecule that shuttles long-chain fatty acids to the mitochondria for oxidation, is thought to be important in preparing the fetus for its lipid-rich postnatal milk diet. Using brush-border membrane (BBM) vesicles from human term placentas, we showed that l-carnitine uptake was sodium and temperature dependent, showed high affinity for carnitine (apparent Km = 11.09 ± 1.32 μM; Vmax = 41.75 ± 0.94 pmol·mg protein−1·min−1), and was unchanged over the pH range from 5.5 to 8.5. l-Carnitine uptake was inhibited in BBM vesicles by valproate, verapamil, tetraethylammonium, and pyrilamine and by structural analogs of l-carnitine, including d-carnitine, acetyl-d,l-carnitine, and propionyl-, butyryl-, octanoyl-, isovaleryl-, and palmitoyl-l-carnitine. Western blot analysis revealed that OCTN2, a high-affinity, Na+-dependent carnitine transporter, was present in placental BBM but not in isolated basal plasma membrane vesicles. The reported properties of OCTN2 resemble those observed for l-carnitine uptake in placental BBM vesicles, suggesting that OCTN2 may mediate most maternofetal carnitine transport in humans.

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22

Palmieri, Orazio, Anna Latiano, Daniela Scimeca, Fabrizio Bossa, Giuseppe Corritore, Tiziana Latiano, Angelo Andriulli, and Vito Annese. "IL23R, ATG16L1, IRGM, OCTN1, and OCTN2 mRNA expression in inflamed and noninflamed mucosa of IBD patients." Inflammatory Bowel Diseases 17, no. 8 (August 2011): 1832–33. http://dx.doi.org/10.1002/ibd.21613.

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23

Broderick, Tom L., Frank A. Cusimano, Chelsea Carlson, and Jeganathan Ramesh Babu. "Biosynthesis of the Essential Fatty Acid Oxidation Cofactor Carnitine Is Stimulated in Heart and Liver after a Single Bout of Exercise in Mice." Journal of Nutrition and Metabolism 2018 (May 29, 2018): 1–7. http://dx.doi.org/10.1155/2018/2785090.

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We determined whether one single bout of exercise stimulates carnitine biosynthesis and carnitine uptake in liver and heart. Free carnitine (FC) in plasma was assayed using acetyltransferase and [14C]acetyl-CoA in Swiss Webster mice after 1 hour of moderate-intensity treadmill running or 4 hours and 8 hours into recovery. Liver and heart were removed under the same conditions for measurement of carnitine biosynthesis enzymes (liver butyrobetaine hydroxylase, γ-BBH; heart trimethyllysine dioxygenase, TMLD), organic cation transporter-2 (OCTN2, carnitine transporter), and liver peroxisome proliferator-activated receptor-alpha (PPARα, transcription factor for γ-BBH and OCTN2 synthesis). In exercised mice, FC levels in plasma decreased while heart and liver OCTN2 protein expressed increased, reflecting active uptake of FC. During recovery, the rise in FC to control levels was associated with increased liver γ-BBH expression. Protein expression of PPARα was stimulated in liver after exercise and during recovery. Interestingly, heart TMLD protein was also detected after exercise. Acute exercise stimulates carnitine uptake in liver and heart. The rapid return of FC levels in plasma after exercise indicates carnitine biosynthesis by liver is stimulated to establish carnitine homeostasis. Our results suggest that exercise may benefit patients with carnitine deficiency syndromes.

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Jakoby, Michael, Amruta Jaju, Aundrea Marsh, and Andrew Wilber. "Maternal Primary Carnitine Deficiency and a Novel Solute Carrier Family 22 Member 5 (SLC22A5) Mutation." Journal of Investigative Medicine High Impact Case Reports 9 (January 2021): 232470962110195. http://dx.doi.org/10.1177/23247096211019543.

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Primary carnitine deficiency (PCD) is a rare autosomal recessive disorder caused by loss of function mutations in the solute carrier family 22 member 5 ( SLC22A5) gene that encodes a high-affinity sodium-ion–dependent organic cation transporter protein (OCTN2). Reduced carnitine transport results in diminished fatty acid oxidation in heart and skeletal muscle and carnitine wasting in urine. We present a case of PCD diagnosed in an adult female after a positive newborn screen (NBS) for PCD that was not confirmed on follow-up testing. The mother was referred for evaluation of persistent fatigue and possible hypothyroidism even though all measurements of thyroid-stimulating hormone were well within the range of 0.4 to 2.5 mIU/L expected for reproductive-age women. She was found to have unequivocally low levels of both total carnitine and carnitine esters, and genetic testing revealed compound heterozygosity for 2 SLC22A5 mutations. One mutation (c.34G>A [p.Gly12Ser]) is a known missense mutation with partial OCTN2 activity, but the other mutation (c.41G>A [p.Trp14Ter]) is previously unreported and results in a premature stop codon and truncated OCTN2. This case illustrates that some maternal inborn errors of metabolism can be identified by NBS and that maternal carnitine levels should be checked after a positive NBS test for PCD.

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Pfeilstocker, Michael, Heidrun Karlic, Peter Wihlidal, Thomas Noesslinger, and Elisabeth Pittermann. "Hypermethylation and Reduced Carnitine Availability - Possible Mechanisms for Downregulation of Microsomal Carnitine Palmitoyltransferase (mCPT) in Myelodysplastic Syndromes (MDS)." Blood 108, no. 11 (November 16, 2006): 2648. http://dx.doi.org/10.1182/blood.v108.11.2648.2648.

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Abstract Hypermethylation of CpG islands within gene promoter regions is associated with transcriptional inactivation of genes involved in cellular proliferation and differentiation and represents, in addition to genetic aberrations, an important mechanism of transcriptional silencing in the pathogenesis of age-associated diseases such as myelodysplastic syndromes (MDS). We have previously reported downregulation of enzymes associated with carnitine-metabolism (including the carnitine transporter OCTN2, which is responsible for carnitine uptake into cells) in healthy elderly persons, as well as a specific downregulation of microsomal carnitine palmitoyltransferase (mCPT; also known as glucose regulated protein GRP58 or endoplasmatic reticulum protein ERp61) a marker for proliferative potential of cells in MDS patients (J.Mol.Med, 81:435ff 2003). Aim of this study was to elucidate the mechanism of this downregulation by analysing the methylation status of the mCPT promoter in 14 MDS patients (2 RA, 5 RARS, 6 RAEB and one CMML). First, mRNA levels of mCPT, as well as a mitochondrial CPT (CPT1A) and OCTN2 were analysed from peripheral blood mononuclear cells using RTQ-PCR (reverse transcriptase quantitative real time PCR). Bisulfite modifications of genomic DNA were performed with commercially available kits (Epigentek, Chemicon, including methylated and unmethylated DNAs as controls) and subsequently analysed by real-time PCR with specific primers for methylated and unmethylated promoter sequences of the mCPT gene. Confirming earlier data, gene-expression of mCPT was reduced in all cases. Association of this downregulation with promoter hypermethylation was detected in 10/14 samples of MDS patients. 2 patients with unmethylated mCPT promoter had characteristic distinct MDS subtype-diagnoses: one RAEB (FAB) with single del(5)(q) and one CMML, thus suggesting different mechanisms of gene silencing in heterogeneous MDS. In two more patients with unmethylated mCPT (one RA and one RARS), relative OCTN2-mRNA-expression was elevated 10 fold as compared to hypermethylated samples, which were characterised by extremely low OCTN2-expression. Since L-carnitine has the potential to induce histone acetylation (J. Med. Genet.2003; 40; 76ff), which prevents hypermethylation of CpG islands, our data may provide an explanation for the concordant downregulation of mCPT and OCTN2 in these cases. In conclusion, our data confirm downregulation of mCPT in MDS. Besides methylation, other factors may also contribute to this phenomenon, because mCPT is located in the microsomal membrane where additionally multiple pre- and postranslational modifications such as prenylation, proteolysis and palmitoylation take place. The exploration of the epigenetic alterations mentioned above may help to develop novel strategies for therapy monitoring as clinical trials using epigenetically targeted therapies have yielded promising results for myelodysplastic syndromes.

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Stack, Laura M., Kris L. Snow, and Richard H. Moseley. "OCTN2 is not a canalicular organic cation transporter." Gastroenterology 118, no. 4 (April 2000): A933. http://dx.doi.org/10.1016/s0016-5085(00)85870-9.

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Lancaster, Cynthia S., Chaoxin Hu, Ryan M. Franke, Kelly K. Filipski, Shelley J. Orwick, Zhaoyuan Chen, Zhili Zuo, Walter J. Loos, and Alex Sparreboom. "Cisplatin-Induced Downregulation of OCTN2 Affects Carnitine Wasting." Clinical Cancer Research 16, no. 19 (September 21, 2010): 4789–99. http://dx.doi.org/10.1158/1078-0432.ccr-10-1239.

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28

Oppedisano, Francesca, Carolina Muscoli, Vincenzo Musolino, Cristina Carresi, Roberta Macrì, Caterina Giancotta, Francesca Bosco, et al. "The Protective Effect of Cynara Cardunculus Extract in Diet-Induced NAFLD: Involvement of OCTN1 and OCTN2 Transporter Subfamily." Nutrients 12, no. 5 (May 15, 2020): 1435. http://dx.doi.org/10.3390/nu12051435.

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Hyperlipidemia and insulin-resistance are often associated with Non-Alcoholic Fatty Liver Disease (NAFLD) thereby representing a true issue worldwide due to increased risk of developing cardiovascular and systemic disorders. Although clear evidence suggests that circulating fatty acids contribute to pathophysiological mechanisms underlying NAFLD and hyperlipidemia, further studies are required to better identify potential beneficial approaches for counteracting such a disease. Recently, several artichoke extracts have been used for both reducing hyperlipidemia, insulin-resistance and NAFLD, though the mechanism is unclear. Here we used a wild type of Cynara Cardunculus extract (CyC), rich in sesquiterpens and antioxidant active ingredients, in rats fed a High Fat Diet (HFD) compared to a Normal Fat Diet (NFD). In particular, in rats fed HFD for four consecutive weeks, we found a significant increase of serum cholesterol, triglyceride and serum glucose. This effect was accompanied by increased body weight and by histopathological features of liver steatosis. The alterations of metabolic parameters found in HFDs were antagonised dose-dependently by daily oral supplementation of rats with CyC 10 and 20 mg/kg over four weeks, an effect associated to significant improvement of liver steatosis. The effect of CyC (20 mg/kg) was also associated to enhanced expression of both OCTN1 and OCTN2 carnitine-linked transporters. Thus, present data suggest a contribution of carnitine system in the protective effect of CyC in diet-induced hyperlipidemia, insulin-resistance and NAFLD.

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Tahara, Harunobu, Sook Wah Yee, Thomas J. Urban, Stephanie Hesselson, Richard A. Castro, Michiko Kawamoto, Doug Stryke, et al. "Functional Genetic Variation in the Basal Promoter of the Organic Cation/Carnitine Transporters OCTN1 (SLC22A4) and OCTN2 (SLC22A5)." Journal of Pharmacology and Experimental Therapeutics 329, no. 1 (January 13, 2009): 262–71. http://dx.doi.org/10.1124/jpet.108.146449.

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30

Fujita, Masaharu, Takeo Nakanishi, Yuta Shibue, Daisuke Kobayashi, Richard H. Moseley, Yoshiyuki Shirasaka, and Ikumi Tamai. "Hepatic uptake of γ-butyrobetaine, a precursor of carnitine biosynthesis, in rats." American Journal of Physiology-Gastrointestinal and Liver Physiology 297, no. 4 (October 2009): G681—G686. http://dx.doi.org/10.1152/ajpgi.00238.2009.

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γ-Butyrobetaine (GBB) is a precursor in the biosynthesis of carnitine, which plays an important role in the β-oxidation of fatty acids, and is converted to carnitine by γ-butyrobetaine dioxygenase (BBD) predominantly in liver. We investigated the molecular mechanism of hepatic uptake of GBB in rat hepatocytes. Cellular localization of rat Octn2 (rOctn2:Slc22A5) was studied by Western blot analysis. Uptake of deuterated GBB (d3-GBB) was examined in HEK293 cells expressing rOctn2 (HEK293/rOctn2) and freshly isolated rat hepatocytes. d3-GBB was quantified by use of liquid chromatography-tandem mass spectrometry. Western blot analysis demonstrated an expression of OCTN2 protein in hepatic basolateral membrane but not in bile canalicular membrane fraction. Furthermore, we found that d3-GBB was taken up by rOctn2 in an Na+-dependent manner with Km value of 13 μM. The apparent Km value for d3-GBB transport in freshly isolated rat hepatocytes was 9 μM. d3-GBB uptake by the rat hepatocytes was inhibited by γ-aminobutyric acid (GABA) to 30% of the control, whereas it was inhibited by carnitine to 62% of the control, even at 500 μM. Furthermore, d3-GBB uptake by rat hepatocytes was decreased by 45% with rat Gat2 (Slc6A13, a major liver GABA transporter) silenced by the microRNA method. Accordingly, the present study clearly demonstrates that GBB is taken up by hepatocytes for carnitine biosynthesis not only via Octn2 but also via the GABA transporter, possibly Gat2.

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Kobayashi, Daisuke, Akihiko Goto, Tomoji Maeda, Jun-ichi Nezu, Akira Tsuji, and Ikumi Tamai. "OCTN2-mediated transport of carnitine in isolated Sertoli cells." Reproduction 129, no. 6 (June 2005): 729–36. http://dx.doi.org/10.1530/rep.1.00507.

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Carnitine is extensively accumulated in epididymis. Carnitine is also accumulated in testis at higher concentration than in the plasma and is used in spite of the presence of the blood–testis barrier. In this study, we examined the characteristics of carnitine transport in primary-cultured rat Sertoli cells, which constitute a part of the blood–testis barrier. Uptake of [3H]carnitine (11.4 nM) from the basal side of Sertoli cells was Na+-dependent and was significantly decreased in the presence of 10 μM (48.0 ± 7.4% of control) or 100 μM unlabeled carnitine (14.6 ± 5.7% of control). Furthermore, the uptake was significantly inhibited in the presence of 100 μM acetyl-L-carnitine, 100 μM gamma-butyrobetaine or 500 μM quinidine. In RT-PCR analysis, the high-affinity carnitine transporter OCTN2 was detected in rat whole testis tissue and primary-cultured Sertoli cells. In contrast, the low-affinity carnitine transporter ATB0,+was detected in rat whole testis tissue, but not in primary cultured Sertoli cells. These results demonstrate that OCTN2 mediates carnitine supply to Sertoli cells from the circulation.

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32

Hu, Chaoxin, Cynthia S. Lancaster, Zhili Zuo, Shuiying Hu, Zhaoyuan Chen, Jeffrey E. Rubnitz, Sharyn D. Baker, and Alex Sparreboom. "Inhibition of OCTN2-Mediated Transport of Carnitine by Etoposide." Molecular Cancer Therapeutics 11, no. 4 (March 2, 2012): 921–29. http://dx.doi.org/10.1158/1535-7163.mct-11-0980.

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33

Furuichi, Yasuro, Tomoko Sugiura, Yukio Kato, Hisashi Takakura, Yoshiteru Hanai, Takeshi Hashimoto, and Kazumi Masuda. "Muscle contraction increases carnitine uptake via translocation of OCTN2." Biochemical and Biophysical Research Communications 418, no. 4 (February 2012): 774–79. http://dx.doi.org/10.1016/j.bbrc.2012.01.101.

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34

Juraszek, Barbara, and Katarzyna A. Nałęcz. "SLC22A5 (OCTN2) Carnitine Transporter—Indispensable for Cell Metabolism, a Jekyll and Hyde of Human Cancer." Molecules 25, no. 1 (December 19, 2019): 14. http://dx.doi.org/10.3390/molecules25010014.

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Oxidation of fatty acids uses l-carnitine to transport acyl moieties to mitochondria in a so-called carnitine shuttle. The process of β-oxidation also takes place in cancer cells. The majority of carnitine comes from the diet and is transported to the cell by ubiquitously expressed organic cation transporter novel family member 2 (OCTN2)/solute carrier family 22 member 5 (SLC22A5). The expression of SLC22A5 is regulated by transcription factors peroxisome proliferator-activated receptors (PPARs) and estrogen receptor. Transporter delivery to the cell surface, as well as transport activity are controlled by OCTN2 interaction with other proteins, such as PDZ-domain containing proteins, protein phosphatase PP2A, caveolin-1, protein kinase C. SLC22A5 expression is altered in many types of cancer, giving an advantage to some of them by supplying carnitine for β-oxidation, thus providing an alternative to glucose source of energy for growth and proliferation. On the other hand, SLC22A5 can also transport several chemotherapeutics used in clinics, leading to cancer cell death.

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35

Gaj, Pawel, Michal Mikula, Lucjan S. Wyrwicz, Jaroslaw Regula, and Jerzy Ostrowski. "Barrett's esophagus associates with a variant of IL23R gene." Acta Biochimica Polonica 55, no. 2 (June 14, 2008): 365–69. http://dx.doi.org/10.18388/abp.2008_3084.

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Gastroesophageal reflux disease is regarded as a spectrum of diseases: non-erosive reflux disease (NERD), erosive reflux disease (ERD), and the far end of the spectrum represented by patients with Barrett's esophagus. Among predisposing factors, both risk and protective polymorphic variants of several genes may influence the clinical outcomes of reflux disease. Consequently, different molecular mechanisms are likely to underlie the development of clinical variants of reflux disease. Ninety six patients with reflux disease were screened for polymorphisms of CARD15, SLC22A4 (OCTN1), SLC22A5 (OCTN2), DLG5, ATG16L1 and IL23R genes which had previously been found to associate with immune-mediated chronic inflammatory disorders. While none of the polymorphisms were associated with NERD or ERD, the 1142G/A variant of the IL23R gene was found to be a risk variant in Barrett's esophagus patients. The IL23/IL23R pathway may modulate STAT3 transcriptional activity which is an essential regulator not only of immune-mediated inflammation, but also of inflammatory-associated apoptosis resistance. Although the mechanisms of metaplastic transition of inflamed squamous epithelium are undetermined as yet, our findings suggest potential involvement of alternations in the IL23/IL23R pathway as a molecular background of Barrett's esophagus development.

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36

Komlósi, K., L. Magyari, G. C. Talián, É. Nemes, R. Káposzta, G. Mogyorósy, K. Méhes, and B. Melegh. "Plasma carnitine ester profile in homozygous and heterozygous OCTN2 deficiency." Journal of Inherited Metabolic Disease 32, S1 (February 24, 2009): 15–19. http://dx.doi.org/10.1007/s10545-009-0926-1.

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37

Gyawali, Asmita, Seung Jae Hyeon, Hoon Ryu, and Young-Sook Kang. "The Alteration of L-Carnitine Transport and Pretreatment Effect under Glutamate Cytotoxicity on Motor Neuron-Like NSC-34 Lines." Pharmaceutics 13, no. 4 (April 14, 2021): 551. http://dx.doi.org/10.3390/pharmaceutics13040551.

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L-Carnitine (LC) is essential for transporting fatty acids to the mitochondria for β-oxidation. This study was performed to examine the alteration of the LC transport system in wild type (WT, NSC-34/hSOD1WT) and mutant type (MT, NSC-34/hSOD1G93A) amyotrophic lateral sclerosis (ALS) models. The uptake of [3H]L-carnitine was dependent on time, temperature, concentration, sodium, pH, and energy in both cell lines. The Michaelis–Menten constant (Km) value as well as maximum transport velocity (Vmax) indicated that the MT cell lines showed the higher affinity and lower capacity transport system, compared to that of the WT cell lines. Additionally, LC uptake was inhibited by organic cationic compounds but unaffected by organic anions. OCTN1/slc22a4 and OCTN2/slc22a5 siRNA transfection study revealed both transporters are involved in LC transport in NSC-34 cell lines. Additionally, slc22a4 and slc22a5 was significantly decreased in mouse MT models compared with that in ALS WT littermate models in the immune-reactivity study. [3H]L-Carnitine uptake and mRNA expression pattern showed the pretreatment of LC and acetyl L-carnitine (ALC) attenuated glutamate induced neurotoxicity in NSC-34 cell lines. These findings indicate that LC and ALC supplementation can prevent the neurotoxicity and neuro-inflammation induced by glutamate in motor neurons.

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38

Di Cristo, Francesca, Anna Calarco, Filomena Anna Digilio, Maria Stefania Sinicropi, Camillo Rosano, Umberto Galderisi, Mariarosa Anna Beatrice Melone, Carmela Saturnino, and Gianfranco Peluso. "The Discovery of Highly Potent THP Derivatives as OCTN2 Inhibitors: From Structure-Based Virtual Screening to In Vivo Biological Activity." International Journal of Molecular Sciences 21, no. 19 (October 8, 2020): 7431. http://dx.doi.org/10.3390/ijms21197431.

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A mismatch between β-oxidation and the tricarboxylic acid cycle (TCA) cycle flux in mitochondria produces an accumulation of lipid metabolic intermediates, resulting in both blunted metabolic flexibility and decreased glucose utilization in the affected cells. The ability of the cell to switch to glucose as an energy substrate can be restored by reducing the reliance of the cell on fatty acid oxidation. The inhibition of the carnitine system, limiting the carnitine shuttle to the oxidation of lipids in the mitochondria, allows cells to develop a high plasticity to metabolic rewiring with a decrease in fatty acid oxidation and a parallel increase in glucose oxidation. We found that 3-(2,2,2-trimethylhydrazine)propionate (THP), which is able to reduce cellular carnitine levels by blocking both carnitine biosynthesis and the cell membrane carnitine/organic cation transporter (OCTN2), was reported to improve mitochondrial dysfunction in several diseases, such as Huntington’s disease (HD). Here, new THP-derived carnitine-lowering agents (TCL), characterized by a high affinity for the OCTN2 with a minimal effect on carnitine synthesis, were developed, and their biological activities were evaluated in both in vitro and in vivo HD models. Certain compounds showed promising biological activities: reducing protein aggregates in HD cells, ameliorating motility defects, and increasing the lifespan of HD Drosophila melanogaster.

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39

Maeda, Tomoji, Takeru Wakasawa, Miho Funabashi, Akimasa Fukushi, Masaharu Fujita, Kiyoto Motojima, and Ikumi Tamai. "Regulation of Octn2 Transporter (SLC22A5) by Peroxisome Proliferator Activated Receptor Alpha." Biological & Pharmaceutical Bulletin 31, no. 6 (2008): 1230–36. http://dx.doi.org/10.1248/bpb.31.1230.

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40

Furuichi, Yasuro, Tomoko Sugiura, Yukio Kato, Hisashi Takakura, Yoshiteru Hanai, and Kazumi Masuda. "Muscle Contraction Increases Carnitine Uptake Via The Cellular Redistribution Of OCTN2." Medicine & Science in Sports & Exercise 43, Suppl 1 (May 2011): 808. http://dx.doi.org/10.1249/01.mss.0000402249.07270.81.

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41

Broderick, Tom L., Frank A. Cusimano, Chelsea Carlson, and Leslie K. Tamura. "Acute Exercise Stimulates Carnitine Biosynthesis and OCTN2 Expression in Mouse Kidney." Kidney and Blood Pressure Research 42, no. 3 (2017): 398–405. http://dx.doi.org/10.1159/000478737.

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42

Kato, Yukio, Yoshimichi Sai, Kazuhiro Yoshida, Chizuru Watanabe, Tadayoshi Hirata, and Akira Tsuji. "PDZK1 Directly Regulates the Function of Organic Cation/Carnitine Transporter OCTN2." Molecular Pharmacology 67, no. 3 (November 2, 2004): 734–43. http://dx.doi.org/10.1124/mol.104.002212.

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43

Urban, Thomas J., Renata C. Gallagher, Chaline Brown, Richard A. Castro, Leah L. Lagpacan, Claire M. Brett, Travis R. Taylor, et al. "Functional Genetic Diversity in the High-Affinity Carnitine Transporter OCTN2 (SLC22A5)." Molecular Pharmacology 70, no. 5 (August 24, 2006): 1602–11. http://dx.doi.org/10.1124/mol.106.028126.

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44

Wang, Gang, Lichun Zhao, Qikun jiang, Yixin Sun, Dongyang Zhao, Mengchi Sun, Zhonggui He, Jin sun, and Yang Wang. "Intestinal OCTN2- and MCT1-targeted drug delivery to improve oral bioavailability." Asian Journal of Pharmaceutical Sciences 15, no. 2 (March 2020): 158–72. http://dx.doi.org/10.1016/j.ajps.2020.02.002.

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45

Pochini, Lorena, Mariafrancesca Scalise, and Cesare Indiveri. "Inactivation by omeprazole of the carnitine transporter (OCTN2) reconstituted in liposomes." Chemico-Biological Interactions 179, no. 2-3 (May 2009): 394–401. http://dx.doi.org/10.1016/j.cbi.2008.10.052.

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46

Angelini, Sabrina, Maria Abbondanza Pantaleo, Gloria Ravegnini, Corrado Zenesini, Giulia Cavrini, Margherita Nannini, Elena Fumagalli, 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." Pharmacological Research 68, no. 1 (February 2013): 1–6. http://dx.doi.org/10.1016/j.phrs.2012.10.015.

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47

Tamai, Ikumi, Rikiya Ohashi, Junichi Nezu, Asuka Oku, Noriyoshi Hashimoto, Hiroko Nikaido, Yoshimichi Sai, Jun-ichiro Hayakawa, Miyuki Shimane, and Akira Tsuji. "Mutation of carnitine transporter OCTN2 in primary systemic carintine deficient jvs mice." Japanese Journal of Pharmacology 79 (1999): 108. http://dx.doi.org/10.1016/s0021-5198(19)34455-5.

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48

Kai, Saori, Kazumichi Yakushiji, Masamichi Yamauchi, Chizuru Ito, Masamichi Kuwajima, Yukio Osada, and Kiyotaka Toshimori. "Expression of novel organic cation/carnitine transporter (OCTN2) in the mouse pancreas." Tissue and Cell 37, no. 4 (August 2005): 309–15. http://dx.doi.org/10.1016/j.tice.2005.04.001.

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49

Ohashi, Rikiya, Ikumi Tamai, Jun-ichi Nezu, Hiroko Nikaido, Noriyoshi Hashimoto, Asuka Oku, Yoshimichi Sai, Miyuki Shimane, and Akira Tsuji. "Molecular and Physiological Evidence for Multifunctionality of Carnitine/Organic Cation Transporter OCTN2." Molecular Pharmacology 59, no. 2 (February 1, 2001): 358–66. http://dx.doi.org/10.1124/mol.59.2.358.

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50

Scalise, Mariafrancesca, Michele Galluccio, Rosita Accardi, Iris Cornet, Massimo Tommasino, and Cesare Indiveri. "Human OCTN2 (SLC22A5) is down-regulated in virus- and nonvirus-mediated cancer." Cell Biochemistry and Function 30, no. 5 (February 28, 2012): 419–25. http://dx.doi.org/10.1002/cbf.2816.

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