CONCLUSION
To understand physiologic and pharmacologic systems, it is critical to identify all of the components or proteins involved in those systems. The last few decades have ushered in a new understanding of the physiologic and pharmacologic roles of important zwitterions and organic cations, as the transporters involved in their absorption and disposition have been identified. It is now clear that transporters in the SLC22 family along with a few other transporters play key roles as determinants of systemic and tissue levels of cationic and zwitterionic drugs. At all levels from molecular to physiologic and pathophysiologic, there are major gaps in our knowledge. First and foremost, transporters for organic cations and zwitterions need to be discovered. With the recent deorphaning of SLC22A15, a key zwitterion transporter was identified in the human genome; however, many transporters remain orphans in the SLC superfamily and, in particular, in the SLC22 family. These transporters need to be deorphaned. Further, no transporter in the SLC22 family has been crystallized; therefore, the precise molecular transport mechanism is not known. Moreover, though many associations have been reproducibly observed between genetic variants in organic cation and zwitterion transporters and various clinical phenotypes, the mechanisms by which the transporter contributes to the phenotypes remain poorly understood. Rare variants in the transporters such as in SLC22A5 (OCTN2) are associated with fatal diseases, yet the function of these variants remain unknown and therapies remain poor at best. Finally, the physiologic, pharmacologic, and pathophysiologic systems that include these transporters need to be fully understood in order to obtain a full understanding of human biology and pharmacology.
REFERENCES
1 [1] Koepsell H, Lips K, Volk C. Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications. Pharm Res 2007; 24(7):1227–1251.
2 [2] Koepsell H. Organic cation transporters in health and disease. Pharmacol Rev 2020; 72(1):253–319.
3 [3] Zhao R, Goldman ID. Folate and thiamine transporters mediated by facilitative carriers (SLC19A1‐3 and SLC46A1) and folate receptors. Mol Aspects Med 2013; 34(2–3):373–385.
4 [4] Engel K, Zhou M, Wang J. Identification and characterization of a novel monoamine transporter in the human brain. J Biol Chem 2004; 279(48):50042–50049.
5 [5] Madeira F, Park YM, Lee J, Buso N, Gur T, Madhusoodanan N, Basutkar P, Tivey ARN, Potter SC, Finn RD, Lopez R. The EMBL‐EBI search and sequence analysis tools APIs in 2019. Nucleic Acids Res 2019; 47(W1):W636–W641.
6 [6] Gene expression levels and immunolocalization of organic ion transporters in the human kidney. J Am Soc Nephrol 2002; 13(4):866–874.
7 [7] Wagner DJ, Hu T, Wang J. Polyspecific organic cation transporters and their impact on drug intracellular levels and pharmacodynamics. Pharmacol Res 2016; 111:237–246.
8 [8] Lin CJ, Tai Y, Huang MT, Tsai YF, Hsu HJ, Tzen KY, Liou HH. Cellular localization of the organic cation transporters, OCT1 and OCT2, in brain microvessel endothelial cells and its implication for MPTP transport across the blood‐brain barrier and MPTP‐induced dopaminergic toxicity in rodents. J Neurochem 2010; 114(3):717–727.
9 [9] Lee N, Duan H, Hebert MF, Liang CJ, Rice KM, Wang J. Taste of a pill: organic cation transporter‐3 (OCT3) mediates metformin accumulation and secretion in salivary glands. J Biol Chem 2014; 289(39):27055–27064.
10 [10] Dakal TC, Kumar R, Ramotar D. Structural modeling of human organic cation transporters. Comput Biol Chem 2017; 68:153–163.
11 [11] Koepsell H. Substrate recognition and translocation by polyspecific organic cation transporters. Biol Chem 2011; 392(1–2):95–101.
12 [12] Volk C. OCTs, OATs, and OCTNs: structure and function of the polyspecific organic ion transporters of the SLC22 family. Wiley Interdiscip Rev Membr Transp Signal 2014; 3(1):1–13.
13 [13] Harper JN, Wright SH. Multiple mechanisms of ligand interaction with the human organic cation transporter, OCT2. Am J Physiol Renal Physiol 2013; 304(1):F56–F67.
14 [14] Egenberger B, Gorboulev V, Keller T, Gorbunov D, Gottlieb N, Geiger D, Mueller TD, Koepsell H. A substrate binding hinge domain is critical for transport‐related structural changes of organic cation transporter 1. J Biol Chem 2012; 287(37):31561–31573.
15 [15] Chien HC, Zur AA, Maurer TS, Yee SW, Tolsma J, Jasper P, Scott DO, Giacomini KM. Rapid method to determine intracellular drug concentrations in cellular uptake assays: application to metformin in organic cation transporter 1‐transfected human embryonic kidney 293 cells. Drug Metab Dispos 2016; 44(3):356–364.
16 [16] Morrissey KM, Wen CC, Johns SJ, Zhang L, Huang SM, Giacomini KM. The UCSF‐FDA TransPortal: a public drug transporter database. Clin Pharmacol Ther 2012; 92(5):545–546.
17 [17] Koepsell H. The SLC22 family with transporters of organic cations, anions and zwitterions. Mol Aspects Med 2013; 34(2–3):413–435.
18 [18] Chen L, Shu Y, Liang X, Chen EC, Yee SW, Zur AA, Li S, Xu L, Keshari KR, Lin MJ, Chien HC, Zhang Y, Morrissey KM, Liu J, Ostrem J, Younger NS, Kurhanewicz J, Shokat KM, Ashrafi K, Giacomini KM. OCT1 is a high‐capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin. Proc Natl Acad Sci U S A 2014; 111(27):9983–9988.
19 [19] Dresser MJ, Gray AT, Giacomini KM. Kinetic and selectivity differences between rodent, rabbit, and human organic cation transporters (OCT1). J Pharmacol Exp Ther 2000; 292(3):1146–1152.
20 [20] Kim HI, Raffler J, Lu W, Lee JJ, Abbey D, Saleheen D, Rabinowitz JD, Bennett MJ, Hand NJ, Brown C, Rader DJ. Fine mapping and functional analysis reveal a role of SLC22A1 in acylcarnitine transport. Am J Hum Genet 2017; 101(4):489–502.
21 [21] Hyrsova L, Smutny T, Carazo A, Moravcik S, Mandikova J, Trejtnar F, Gerbal‐Chaloin S, Pavek P. The pregnane X receptor down‐regulates organic cation transporter 1 (SLC22A1) in human hepatocytes by competing for (“squelching”) SRC‐1 coactivator. Br J Pharmacol 2016; 173(10):1703–1715.
22 [22] Hyrsova L, Smutny T, Trejtnar F, Pavek P. Expression of organic cation transporter 1 (OCT1): unique patterns of indirect regulation by nuclear receptors and hepatospecific gene regulation. Drug Metab Rev 2016; 48(2):139–158.
23 [23] Ciarimboli G, Deuster D, KNIEF A, Sperling M, Holtkamp M, Edemir B, Pavenstädt H, Lanvers‐Kaminsky C, Am Zehnhoff‐Dinnesen A, Schinkel AH, Koepsell H, Jürgens H, Schlatter E. Regulation of the human organic cation transporter hOCT1. J Cell Physiol 2004; 201(3):420–428.
24 [24] Jonker JW, Wagenaar E, Mol CA, Buitelaar M, Koepsell H, Smit JW, Schinkel AH. Reduced hepatic uptake and intestinal excretion of organic cations in mice with a targeted disruption of the organic cation transporter 1 (Oct1 [Slc22a1]) gene. Mol Cell Biol 2001; 21(16):5471–5477.
25 [25] Wang DS, Jonker JW, Kato Y, Kusuhara H, Schinkel AH, Sugiyama Y. Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. J Pharmacol Exp Ther 2002; 302(2):510–515.
26 [26] Wang DS, Kusuhara H, Kato Y, Jonker JW, Schinkel AH, Sugiyama Y. Involvement of organic cation transporter 1 in the lactic acidosis caused by metformin. Mol Pharmacol 2003; 63(4):844–848.
27 [27] Morse BL, Kolur A, Hudson LR, Hogan AT, Chen LH, Brackman RM, Sawada GA, Fallon JK, Smith PC, Hillgren KM. Pharmacokinetics of organic cation transporter 1 (OCT1) substrates in Oct1/2 knockout mice and species difference in hepatic OCT1‐mediated uptake. Drug Metab Dispos 2020; 48(2):93–105.
28 [28] Kerb R, Brinkmann U, Chatskaia
