Octn2 - rat

Octn2 (organic cation / carnitine transporter 2), rat

Aliases: CT1, UST2r
Gene name:  Solute carrier family 22 member 5 (SLC22A5)

Rat Octn2 (organic cation/carnitine transporter novel type 2) is a specific sodium/L-carnitine co-transporter [1]. OCTN2/Octn2 was one of the first uptake transporters cloned from rat [1, 2], human [3] and mouse [4] tissues, respectively. Expression of OCTN2/Octn2 is relatively ubiquitous [5]. In general, tissue distribution of OCTN2/Octn2 is similar in human and rats [6-12], while a few differences do exist in function. OCTN2/Octn2-mediated organic cation transport is pH-sensitive [13, 14].
Human and rat OCTN2/Octn2 show an overlapping but somewhat different substrate and inhibitor specificity. Transport properties of rat Octn2 and human OCTN2 expressed on the same genetic background using L-carnitine, a physiological substrate, and mildronate, the most efficiently transported drug was correlated by Szabó and coworkers [15]. The data indicated that Octn2 has substrate specificity similar to that of OCTN2; however, human OCTN2 has a higher affinity for L-carnitine compared to that of rat Octn2. As free L-carnitine levels are close to its total plasma levels (20-60 µM) [16, 17], the in vitro data also means that the transporters operate at or close to maximum rates in humans and rats to supply carnitine to tissues in vivo. A similar difference was observed in the affinity of OCTN2/Octn2 towards mildronate. Furthermore, many pharmacologically important drugs were shown to affect L-carnitine transport by OCTN2/Octn2. The transporters from these two species showed different but overlapping inhibitor specificities as the differences in IC50 values were less than 3-fold for 13 of 15 compounds tested.
These data suggest that in vivo rat preclinical models may be applicable to predict human OCTN2-mediated toxicity and adverse events in the clinic, but in vitro differences between Octn2/OCTN2 transporter profiles should be taken into account.

References

1.    Schomig, E., et al., Molecular cloning and characterization of two novel transport proteins from rat kidney. FEBS Lett, 1998. 425(1): p. 79-86.
2.    Sekine, T., et al., Molecular cloning and characterization of high-affinity carnitine transporter from rat intestine. Biochem Biophys Res Commun, 1998. 251(2): p. 586-91.
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.    Tamai, I., et al., Molecular and functional characterization of organic cation/carnitine transporter family in mice. J Biol Chem, 2000. 275(51): p. 40064-72.
5.    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.
6.    Furuichi, Y., et al., Muscle contraction increases carnitine uptake via translocation of OCTN2. Biochem Biophys Res Commun, 2012. 418(4): p. 774-9.
7.    Inazu, M., et al., Functional expression of the organic cation/carnitine transporter 2 in rat astrocytes. J Neurochem, 2006. 97(2): p. 424-34.
8.    Koepsell, H. and H. Endou, The SLC22 drug transporter family. Pflugers Arch, 2004. 447(5): p. 666-76.
9.    Nishimura, M. and S. Naito, Tissue-specific mRNA expression profiles of human ATP-binding cassette and solute carrier transporter superfamilies. Drug Metab Pharmacokinet, 2005. 20(6): p. 452-77.
10.    Okura, T., S. Kato, and Y. Deguchi, Functional expression of organic cation/carnitine transporter 2 (OCTN2/SLC22A5) in human brain capillary endothelial cell line hCMEC/D3, a human blood-brain barrier model. Drug Metab Pharmacokinet, 2014. 29(1): p. 69-74.
11.    Sekine, T., et al., Cloning, functional characterization, and localization of a rat renal Na+-dicarboxylate transporter. Am J Physiol, 1998. 275(2 Pt 2): p. F298-305.
12.    Terada, T., et al., Expression profiles of various transporters for oligopeptides, amino acids and organic ions along the human digestive tract. Biochem Pharmacol, 2005. 70(12): p. 1756-63.
13.    Koepsell, H., Polyspecific organic cation transporters: their functions and interactions with drugs. Trends Pharmacol Sci, 2004. 25(7): p. 375-81.
14.    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.
15.    Szabo, K., et al., Species specificity profiling of rat and human organic cation/carnitine transporter Slc22a5/SLC22A5 (Octn2/OCTN2). Drug Metab Pharmacokinet, 2016.
16.    Borum, P.R., Variation in tissue carnitine concentrations with age and sex in the rat. Biochem J, 1978. 176(3): p. 677-81.
17.    Kepka, A., et al., Plasma carnitine concentrations after chronic alcohol intoxication. Postepy Hig Med Dosw (Online), 2013. 67: p. 548-52.

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