![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
PERSPECTIVES IN PHARMACOLOGY
The Netherlands Cancer Institute, Division of Experimental Therapy, Amsterdam, The Netherlands
Received September 30, 2003; accepted October 23, 2003.
 |
Abstract |
|---|
Whereas most of these transporters are highly specialized, mediating facilitated transport of essential nutrients (e.g., glucose, amino acids, nucleosides, and fatty acids), some members are more generalized. Due to their broad substrate specificity, the latter are also termed polyspecific transporters. They play a major role in the elimination of, and protection against, noxious compounds.
Among the SLC superfamily, two families (SLC21 and 22) with polyspecific members have been identified, together mediating the transport of a variety of structurally diverse organic anions, cations, and uncharged compounds. The SLC21 family of organic anion transporting polypeptides currently consists of nine members in humans, transporting a range of relatively large (usually >450 Da), mostly anionic amphipathic compounds, including bile salts, eicosanoids, steroid hormones, and their conjugates (for review, see Hagenbuch and Meier, 2003
). The SLC22 family currently consists of 12 members in humans and rats, encompassing organic cation transporters (OCTs), the carnitine transporter (OCTN2/SLC22A5) (Wu et al., 1998b), the urate anion-exchanger (URAT1/SLC22A12) (Enomoto et al., 2002), and several organic anion transporters (for review, see Sweet et al., 2001). In this review, we focus on the polyspecific organic cation transporters (OCT1, 2, and 3) that belong to the family SLC22 (Koepsell and Endou, 2003; Koepsell et al., 2003).
|
Cloning and Functional Characteristics |
|---|
). In this initial study, it was shown that rOCT1 had functional characteristics similar to the previously described organic cation transport process in the basolateral membrane of renal proximal tubules and hepatocytes. rOCT1 encodes a 556-amino acid protein and has a proposed secondary structure displaying 12 transmembrane domains (TMD). It contains a large extracellular loop, located between the first and second TMD, with three predicted N-linked glycosylation sites (Meyer-Wentrup et al., 1998) that may be involved in protein stability, intracellular routing, or protection from extracellular proteases (Fig. 1). Currently, mammalian orthologs of OCT1 have been cloned from mouse (Schweifer and Barlow, 1996), human (Gorboulev et al., 1997; Zhang et al., 1997b), and rabbit (Terashita et al., 1998).
|
By homology screening, a second member of the organic cation transporter family, designated OCT2 (SLC22A2), was isolated from rat kidney (Okuda et al., 1996) and later also cloned from human (Gorboulev et al., 1997), pig (Gründemann et al., 1997), mouse (Mooslehner and Allen, 1999), and rabbit (Zhang et al., 2002). rOCT2 encodes a 593-amino acid protein with a calculated molecular mass of 66 kDa and 67% identity with rOCT1. The third member of the organic cation transporter family, designated OCT3 (SLC22A3), was independently cloned and identified as the extraneuronal monoamine transporter (EMT, see section catecholamine transport) by two different groups (Gründemann et al., 1998b; Kekuda et al., 1998; Wu et al., 1998a) and later also cloned from mouse (Verhaagh et al., 1999). rOCT3 encodes a 551-amino acid protein with a predicted molecular mass of 61 kDa and 48% identity with rOCT1 (Kekuda et al., 1998).
The functional characteristics of these transporters have been extensively investigated using cRNA injected Xenopus laevis oocytes and transfected mammalian cell lines. OCT1, 2, and 3 all mediate the facilitated transport of a broad range of structurally diverse organic cations, and they have extensively overlapping substrate specificities. In general, the OCTs mediate the (bidirectional) transport of small hydrophilic compounds, ranging in size from about 60 to 350 Da, with at least one positively charged amine moiety at physiological pH. Although many compounds have been shown to inhibit or modulate transport activity of the OCTs, not all of them are transported substrates. Substrates for which transport has been directly demonstrated include the model substrate tetraethylammonium (TEA), the parkinsonian neurotoxin 1-methyl-4-phenylpyridinium (MPP+), clinically used drugs such as antiparkinsonians (amantadine and memantine), antidiabetics (biguanides) and the H2 receptor agonist cimetidine, biogenic amines (dopamine, norepinephrine), and several other endogenous compounds (choline and creatinine). In addition to organic cations, it has also been demonstrated that hOCT1 and hOCT2 mediate the transport of some anionic prostaglandins (Kimura et al., 2002), indicating that a positive charge is no absolute prerequisite for OCT substrates (Table 1).
|
|
Expression and Subcellular Localization |
|---|
). In humans, hOCT1 is primarily expressed in the liver, indicating a difference in tissue distribution of OCT1 between humans and rodents (Gorboulev et al., 1997; Zhang et al., 1997b). OCT2 mRNA was detected predominantly in the kidney in rats and humans (Okuda et al., 1996; Gorboulev et al., 1997). The tissue distribution and subcellular localization of OCT1 and OCT2 have been analyzed by immunohistochemistry in rats and humans (Meyer-Wentrup et al., 1998; Karbach et al., 2000; Sugawara-Yokoo et al., 2000; Motohashi et al., 2002). In the liver, rOCT1 was detected in sinusoidal membranes of hepatocytes around the central veins of the hepatic lobuli. In the kidney, rOCT1 was mainly observed in the pars convoluta (S1) and cortical pars recta (S2) of the proximal tubules, with lower expression in the medullary pars recta (S3), whereas rOCT2 was mainly expressed in the S2 and S3 segments (Meyer-Wentrup et al., 1998; Karbach et al., 2000). By Western analysis, using isolated renal basolateral and brush-border (apical) membranes of proximal tubules, it was shown that both rOCT1 and rOCT2 are localized basolaterally (Urakami et al., 1998; Karbach et al., 2000) (Fig. 2).
|
In addition to the kidney, OCT2 is also expressed in various regions of the brain. By RT-PCR, rOCT2 was detected in dopamine-rich areas of the brain: substantia nigra, nucleus accumbens, and striatum (Gründemann et al., 1997). In humans, hOCT2 was detected by in situ hybridization and immunohistochemistry in the pyramidal cells of the cerebral cortex and hippocampus. In the brain, OCT2 might represent a "background" transporter for the removal of monoamine neurotransmitters that have escaped reuptake by high-affinity monoamine transporters, which are not members of the OCT family (Busch et al., 1998). In contrast to what has been reported by Gründemann et al. (1997), rOCT2 (and rOCT3) was also detected by RT-PCR in the choroid plexus (Sweet et al., 2001). Transfection of intact choroid plexus with an rOCT2-GFP fusion protein construct resulted in strong apical membrane fluorescence with no detectable signal in the basal and lateral membranes, suggesting that rOCT2 mediates transport across the ventricular membrane of the choroid plexus (Sweet et al., 2001).
Expression of OCT2 in the kidney is gender-dependent (Urakami et al., 1999, 2000; Slitt et al., 2002). Starting from the observation that the uptake of TEA by renal cortical slices of male rats is greater than that by females, Urakami et al. (1999) found significantly higher levels of rOCT2 mRNA and protein in the kidney of males compared with females. Moreover, the expression of OCT2 in the kidney was demonstrated to be age-dependent. Whereas in young rats, levels of OCT2 mRNA between males and females were similar, they increased dramatically in males at the age of 30 days (Slitt et al., 2002). Treatment of male and female rats with testosterone significantly increased the expression of rOCT2 in the kidney and stimulated the uptake of TEA in renal slices. Estradiol treatment on the other hand caused a decrease in the expression of rOCT2 and in the uptake of TEA in renal slices, but only in male rats (Urakami et al., 2000). The roles of these steroid hormones were confirmed in gonadectomized rats, where the levels of rOCT2 in the kidney became similar between males and females (Slitt et al., 2002). Together, these studies suggest that rOCT2 is responsible for the gender differences in the renal elimination of organic cations. Although the physiological function of this sexual dimorphism is unknown, it might be responsible for some of the gender-based differences in drug response and sensitivity in patients.
In contrast to OCT1 and OCT2, which are predominantly expressed in the major excretory organs, OCT3 has a much more widespread tissue distribution. Initially, in a limited study, hOCT3 was detected by RT-PCR analysis in brain cortex, heart, and liver (Gründemann et al., 1998b). In a more extensive study, hOCT3 mRNA was detected at high levels in aorta, skeletal muscle, prostate, adrenal gland, salivary gland, liver, term placenta, and fetal lung (Verhaagh et al., 1999). In rats, expression of rOCT3 as analyzed by Northern analysis was highest in intestine and placenta, intermediate in brain and heart, low in kidney and lung, but undetectable in liver (Kekuda et al., 1998). By in situ hybridization, rOCT3 was detected in different regions of the brain, especially in the cerebellum, hippocampus, pontine nucleus, and cerebral cortex, whereas by immunocytochemical staining, hOCT3 was detected in normal human astrocytes (Wu et al., 1998a; Inazu et al., 2003). Rajan et al. (2000) found that in mice mOCT3 mRNA is also expressed in the retinal pigment epithelium of the eye, suggesting involvement of OCT3 in the clearance of dopamine and histamine from the subretinal spaces and possibly in the disposition of neurotoxins such as MPP+. As yet, there is not conclusive published evidence showing whether OCT3 is localized in the basolateral or apical membrane of polarized cells.
|
Catecholamine Transport |
|---|
) as a low-affinity uptake system for catecholamines in isolated rat heart. It was independently cloned by two different groups and was designated EMT/OCT3 (Gründemann et al., 1998b; Kekuda et al., 1998; Wu et al., 1998a). In addition to EMT/OCT3, OCT1 and OCT2 have also been shown to mediate the transport of catecholamines and other biogenic amines (Breidert et al., 1998; Gründemann et al., 1998b). Neuronal reuptake by uptake-1 is quantitatively most important for the clearance of released catecholamines, accounting for about 90% of their removal at the nerve endings. Although OCT3 has been proposed to be the classical EMT, the three OCTs together are thought to be responsible for the (predominantly) extraneuronal clearance of catecholamines that have escaped from reuptake by uptake-1 (for review, see Eisenhofer, 2001). |
Alternative Splicing of OCTs |
|---|
). Alternative splicing allows a single gene to produce a variety of proteins with altered tissue distribution, localization, regulation, or function. Zhang et al. (1997a) identified an alternatively spliced isoform of OCT1 in rat kidney, named rOCT1A, that is generated by skipping of exon 2. As a consequence of this deletion, the rOCT1A transcript encodes a truncated protein of 430 residues (rOCT1 has 556 residues) lacking the first two N-terminal TMDs and the large extracellular loop. Surprisingly, the absence of the first two TMDs has no significant effect on the transport of TEA as tested in RNA-injected oocytes, indicating that they are not essential, at least for the transport of this compound. The tissue distribution of rOCT1A RNA was similar to that of rOCT1, but the physiological function of this splice variant, if any, is as yet unknown (Zhang et al., 1997a).
Hayer et al. (1999) identified several alternatively spliced isoforms of OCT1 in human cells. By RT-PCR, four different transcripts representing variants of hOCT1 were identified in the human glioma cell line SK-MG-1, and two of these were also found in human liver. Further analysis showed that these transcripts represented the full-length hOCT1 and three shorter alternatively spliced isoforms, two of which are lacking the last two C-terminal TMDs and one the last six TMDs. Functional analysis by measuring the uptake of MPP+ in transfected human embryonic kidney 293 cells indicated that neither one of the hOCT1 splice variants exhibited significant decynium-22-sensitive uptake of MPP+. Whether the transport of other substrates is affected in these isoforms is not known.
For OCT2, an alternatively spliced variant was isolated from human kidney (Urakami et al., 2002). This variant, named hOCT2-A, contains a premature stop codon due to an intron splicing error, failing to remove the intron between exon 7 and 8. The open reading frame of this transcript encodes a 483-amino acid protein with 81% amino acid identity with hOCT2 (which consists of 555 amino acids). As a consequence of the premature termination of translation, hOCT2-A consists of only nine TMDs instead of 12, lacking the last three C-terminal TMDs. The tissue distribution of hOCT2 and hOCT2-A RNAs were somewhat different; hOCT2-A was found primarily in kidney, but mRNA was also detected in brain, liver, colon, skeletal muscle, testis, and placenta. In contrast, hOCT2 was detected in kidney, brain, testis, and placenta. Functional analysis using transfected human embryonic kidney 293 cells demonstrated that hOCT2-A still exhibited transport activity of TEA similar to that of hOCT2, but transport of MPP+ and cimetidine were decreased and that of guanidine was abolished. Whether the distinct substrate specificity and tissue distribution of hOCT2-A have any physiological or pharmacological relevance is unclear.
|
Genetic Variations in OCTs |
|---|
; Leabman et al., 2002, 2003; Saito et al., 2002; Lazar et al., 2003; Shu et al., 2003). For OCT1, Kerb et al. (2002) identified among a population of 57 healthy Caucasians, 25 genetic variants, eight of which resulted in amino acid substitutions. Functional characterization, by measuring the uptake of various OCT1 substrates in RNA-injected oocytes, demonstrated reduced transport activity in three of these variants (Arg61Cys, Cys88Arg, and Gly401Ser). Among 247 subjects of diverse ethnic backgrounds, Leabman et al. (2003) identified 15 nonsynonymous polymorphisms in OCT1, four (Arg61Cys, Gly220Val, Gly401Ser, Gly465Arg) resulting in reduced, and one (Ser14Phe) in increased uptake of MPP+ (Shu et al., 2003).
Within the same population, 28 polymorphisms were detected in OCT2, eight of which resulted in nonsynonymous amino acid substitutions (Leabman et al., 2002). Two of these variants, each with an allelic frequency of more than 1% in the African-American population (Met165Ile and Arg400Cys), displayed a significantly reduced transport activity. The variant with the highest allelic frequency (Ala270Ser) had a prevalence of about 12.7% among all different ethnic groups but had a more subtle effect on hOCT2 function. Overall, the frequency of synonymous changes was higher than that of nonsynonymous changes, suggesting an evolutionarily preserved function of hOCT2 (Leabman et al., 2002).
The positions of the mutations and their effects on transport activity and specificity may provide insight into the molecular mechanism by which substrates are recognized and transported by the organic cation transporters. Arg61, Cys88 (hOCT1) and Met165 (hOCT2) are localized in the first large extracellular loop and TMD-2, respectively. The severe effect of these mutations on transport activity is surprising, because complete absence of TMD-1 and -2 has previously been shown to have no significant consequences for the transport of TEA by rOCT1 (Zhang et al., 1997a). Possibly, this part of the protein plays a role in the substrate selectivity but is not essential for basic transport activity. Gly401 (hOCT1) and Arg400 (hOCT2) belong to a stretch of five amino acids that is highly conserved within the superfamily of facilitated transporters, indicating that this sequence might be essential for basal transport activity (Gorboulev et al., 1997).
Based on the allelic frequencies of the above-mentioned variants with (severe) effects on OCT function (about 1%), one would expect that homozygotes for these alleles would arise in the human population with a frequency of about 1 per 10,000 individuals. Interestingly, OCT2 and OCT3 in mice are only expressed from the maternal allele. Together with the Igf2r gene, they form a gene cluster that has been shown to be paternally imprinted in mice (Zwart et al., 2001a). It is not known whether OCT2 and OCT3 are also imprinted in humans, but if so, this implicates that the actual frequency of humans with a partial or complete deficiency in OCT2 might be much higher. The possible clinical and physiological consequences of a genetic deficiency in the organic cation transporters are discussed in the next section.
|
Knockout Mouse Models |
|---|
, 2003; Zwart et al., 2001b).
Oct1-deficient mice are viable and healthy and display no obvious phenotypical abnormalities, indicating that Oct1 is not essential for normal physiological functioning in mice. However, absence of Oct1 does have a pronounced effect on the pharmacokinetics of substrate organic cations. In Oct1-/- mice, the accumulation in liver of intravenously administered TEA was dramatically reduced (by 85 and 77% after 20 and 60 min, respectively) compared with wild-type mice, indicating that Oct1 is the main sinusoidal uptake system for TEA in the liver. In addition, direct small intestinal excretion of TEA in Oct1-/- mice was reduced by about 50%. This indicated that Oct1 also mediates the basolateral uptake of TEA into enterocytes, which is necessary for subsequent excretion into the gut lumen (Jonker et al., 2001). Together, these findings may be of clinical importance because they might help predicting and analyzing the consequences of a deficiency in OCT1 in humans. A genetic deficiency in OCT1 could have both positive and negative consequences for drug therapy. On the one hand, reduced hepatic uptake of drugs may result in a decreased therapeutic efficacy of drugs that have their desired pharmacodynamic action (or metabolic activation) in the liver. On the other hand, reduced hepatic uptake of drugs could be beneficial for drugs that have adverse side effects in the liver. The latter is exemplified by the biguanide metformin, an antidiabetic drug that displays reduced hepatic uptake and toxicity in Oct1-/- mice (Wang et al., 2002, 2003). Biguanides form a class of drugs widely used for the treatment of hyperglycemia in patients with type 2 diabetes mellitus. The biguanides metformin, buformin, and phenformin are excellent substrates of OCT1 as demonstrated in vitro in rOCT1-transfected Chinese hamster ovary cells (Wang et al., 2002). A severe, sometimes lethal toxic side effect of the biguanides is lactic acidosis (i.e., accumulation of lactate in plasma), which is thought to result from interference with processes in the liver. For this reason, phenformin was withdrawn from clinical use in many countries in the late 1970s. In Oct1-/- mice the accumulation of metformin into the liver was more than 30-fold reduced compared with wild-type mice (Wang et al., 2002). Coincident with this decreased hepatic accumulation, metformin-induced levels of blood lactate were significantly decreased in Oct1-/- mice, indicating the involvement of Oct1 in processes leading to lactic acidosis (Wang et al., 2003).
The absence of Oct1 from the liver also resulted in a shift in the elimination of transported drugs from hepatobiliary toward renal elimination. Consequently, the urinary excretion of drugs in Oct1-/- mice was increased instead of decreased, contrary to what was initially expected (Jonker et al., 2001; Wang et al., 2002). The analysis of the role of Oct1 in renal drug secretion in mice was also complicated by its functional redundancy with Oct2. Therefore, to further analyze the role of these transporters in the renal secretion, we generated Oct2 single knockout and Oct1/2 double knockout mice (Jonker et al., 2003). Like for Oct1, a deficiency in Oct2 and a combined deficiency in Oct1 and Oct2 had no obvious effect on the physiology of mice. Absence of Oct2 in itself had little effect on the pharmacokinetics of TEA, but in Oct1/2-/- mice, the renal secretion of this compound was completely abolished, leaving only glomerular filtration as an excretion mechanism for TEA. As a consequence, plasma levels of TEA were substantially elevated in Oct1/2-/- mice (Jonker et al., 2003). Unlike rodents that express both Oct1 and Oct2 in the kidney, humans express only OCT2 in kidney (Gründemann et al., 1998a). Therefore, it is likely that the Oct1/2-/- mouse model better reflects the effect of an OCT2 deficiency on kidney function in humans than the Oct2-/- mouse model. Thus, based on our findings, we expect that humans with a deficiency in OCT2 will have an impaired renal secretion of some drugs, which may result in increased drug exposure.
Oct3-deficient mice have been generated by Zwart et al. (2001). Oct3-/- mice are viable and fertile and show no apparent neural or physiological defect or imbalance of the monoamine neurotransmitters norepinephrine and dopamine. A clear effect, however, was observed on the uptake of MPP+ into the heart. The heart was originally identified as one of the main uptake-2 sites, and it expresses high levels of OCT3 (Iversen, 1965; Gründemann et al., 1998b). After intravenous administration, accumulation of MPP+ into the heart was reduced by 72% in Oct3-/- mice compared with wild-type mice. In addition, the placenta was identified as a novel uptake-2 site. In pregnant females of an Oct3 heterozygous cross, the accumulation of intravenously administered MPP+ into Oct3-/- fetuses was 3-fold reduced compared to wild-type fetuses. In the placenta, Oct3 colocalizes with the monoamine degrading enzyme monoamine oxidase A, suggesting that together they might form a functional elimination pathway for monoamines produced in the embryo (Zwart et al., 2001b). The lack of effect of absence of OCT3 from other sites, such as the kidney, is most likely due to the functional redundancy between the different OCTs and might be further analyzed in combined knockouts of these transporters.
|
Conclusions and Perspectives |
|---|
The relevance of these transporters for the transport and elimination of endogenous compounds on the other hand is still unclear. It should be realized, however, that the homeostasis of endogenous compounds such as the monoamine neurotransmitters and other hormones is strictly regulated at the levels of production, degradation, and clearance, and an imbalance at one of these levels is likely to be readily compensated. In addition, as we observed for OCT1 and OCT2 in the mouse kidney, considerable functional redundancies may exist between the different transporters. For this reason, it would be of interest to study the effects of a combined deficiency in OCT1, OCT2, and OCT3 in mice as well as that of complementary apical transporters. We would like to add that the relatively safe and sanitized conditions under which laboratory mice are usually housed may not be optimal for identifying all physiological and toxicological functions. Physiological aberrations can be subtle or become only apparent under specific conditions and might be easily missed unless looked for specifically.
With the identification of functionally important genetic polymorphic variants in the human OCT1 and OCT2 genes, it will be of great interest to determine whether these polymorphisms also correlate with altered drug response and sensitivity in patients. If indeed the findings in the knockout mice can be extrapolated to humans, these mouse models will provide powerful tools for predicting and explaining differences in drug (hyper)sensitivity and toxicity between patients. We expect that in the future, the increased understanding of the function of the organic cation transporters may lead to improvement of the design and use of drugs and drug therapies.
|
Footnotes |
|---|
ABBREVIATIONS: SLC, solute carrier superfamily; OCT, organic cation transporter in human and rat; TMD, transmembrane domain; EMT, extraneuronal monoamine transporter; TEA, tetraethylammonium; MPP+, 1-methyl-4-phenylpyridinium; RT-PCR, reverse transcription-polymerase chain reaction; Oct, organic cation transporter in mice.
Address correspondence to: Dr. Johan W. Jonker, Division of Experimental Therapy, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. E-mail: h.jonker{at}nki.nl
|
References |
|---|
Breidert T, Spitzenberger F, Gründemann D, and Schömig E (1998) Catecholamine transport by the organic cation transporter type 1 (OCT1). Br J Pharmacol 125: 218-224.[CrossRef][Medline]
Bloom and Fawcett (1994) A Textbook of Histology, 12th ed.. Chapman & Hall, New York.
Busch AE, Karbach U, Miska D, Gorboulev V, Akhoundova A, Volk C, Arndt P, Ulzheimer JC, Sonders MS, Baumann C, et al. (1998) Human neurons express the polyspecific cation transporter hOCT2, which translocates monoamine neurotransmitters, amantadine and memantine. Mol Pharmacol 54: 342-352.
Busch AE, Quester S, Ulzheimer JC, Gorboulev V, Akhoundova A, Waldegger S, Lang F, and Koepsell H (1996a) Monoamine neurotransmitter transport mediated by the polyspecific cation transporter rOCT1. FEBS Lett 395: 153-156.[CrossRef][Medline]
Busch AE, Quester S, Ulzheimer JC, Waldegger S, Gorboulev V, Arndt P, Lang F, and Koepsell H (1996b) Electrogenic properties and substrate specificity of the polyspecific rat cation transporter rOCT1. J Biol Chem 271: 32599-32604.
Chen R and Nelson JA (2000) Role of organic cation transporters in the renal secretion of nucleosides. Biochem Pharmacol 60: 215-219.[CrossRef][Medline]
Eisenhofer G (2001) The role of neuronal and extraneuronal plasma membrane transporters in the inactivation of peripheral catecholamines. Pharmacol Ther 91: 35-62.[CrossRef][Medline]
Enomoto A, Kimura H, Chairoungdua A, Shigeta Y, Jutabha P, Cha SH, Hosoyamada M, Takeda M, Sekine T, Igarashi T, et al. (2002) Molecular identification of a renal urate-anion exchanger that regulates blood urate levels. Nature (Lond) 417: 447-452.[Medline]
Goralski KB, Lou G, Prowse MT, Gorboulev V, Volk C, Koepsell H, and Sitar DS (2002) The cation transporters rOCT1 and rOCT2 interact with bicarbonate but play only a minor role for amantadine uptake into rat renal proximal tubules. J Pharmacol Exp Ther 303: 959-968.
Gorboulev V, Ulzheimer JC, Akhoundova A, Ulzheimer-Teuber I, Karbach U, Quester S, Baumann C, Lang F, Busch AE, and Koepsell H (1997) Cloning and characterization of two human polyspecific organic cation transporters. DNA Cell Biol 16: 871-881.[Medline]
Gründemann D, Babin-Ebell J, Martel F, Ording N, Schmidt A, and Schömig E (1997) Primary structure and functional expression of the apical organic cation transporter from kidney epithelial LLC-PK1 cells. J Biol Chem 272: 10408-10413.
Gründemann D, Gorboulev V, Gambaryan S, Veyhl M, and Koepsell H (1994) Drug excretion mediated by a new prototype of polyspecific transporter. Nature (Lond) 372: 549-552.[CrossRef][Medline]
Gründemann D, Hahne C, Berkels R, and Schömig E (2003) Agmatine is efficiently transported by non-neuronal monoamine transporters extraneuronal monoamine transporter (EMT) and organic cation transporter 2 (OCT2). J Pharmacol Exp Ther 304: 810-817.
Gründemann D, Koster S, Kiefer N, Breidert T, Engelhardt M, Spitzenberger F, Obermuller N, and Schömig E (1998a) Transport of monoamine transmitters by the organic cation transporter type 2, OCT2. J Biol Chem 273: 30915-30920.
Gründemann D, Liebich G, Kiefer N, Koster S, and Schömig E (1999) Selective substrates for non-neuronal monoamine transporters. Mol Pharmacol 56: 1-10.
Gründemann D, Schechinger B, Rappold GA, and Schömig E (1998b) Molecular identification of the corticosterone-sensitive extraneuronal catecholamine transporter. Nat Neurosci 1: 349-351.[CrossRef][Medline]
Hagenbuch B and Meier PJ (2003) The superfamily of organic anion transporting polypeptides. Biochim Biophys Acta 1609: 1-18.[Medline]
Hayer M, Bönisch H, and Brüss M (1999) Molecular cloning, functional characterization and genomic organization of four alternatively spliced isoforms of the human organic cation transporter 1 (hOCT1/SLC22A1). Ann Hum Genet 63: 473-482.[CrossRef][Medline]
Inazu M, Takeda H, and Matsumiya T (2003) Expression and functional characterization of the extraneuronal monoamine transporter in normal human astrocytes. J Neurochem 84: 43-52.[CrossRef][Medline]
Iversen LL (1965) The uptake of catecholamines at high perfusion concentrations in the rat isolated heart: a novel catecholamine uptake process. Br J Pharmacol 25: 18-33.
Jonker JW, Wagenaar E, Mol CA, Buitelaar M, Koepsell H, Smit JW, and Schinkel AH (2001) 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 21: 5471-5477.
Jonker JW, Wagenaar E, Van Eijl S, and Schinkel AH (2003) Deficiency in the organic cation transporters 1 and 2 (Oct1 and Oct2 [Slc22a1 and Slc22a2]) in mice abolishes the renal secretion of organic cations. Mol Cell Biol 23: 7902-7908.
Junqueira LC, Carneiro J, and Kelley RO (1998) Basic Histology, 9th ed. Appleton & Lange, Stamford, CT.
Kan Z, Rouchka EC, Gish WR, and States DJ (2001) Gene structure prediction and alternative splicing analysis using genomically aligned ESTs. Genome Res 11: 889-900.
Karbach U, Kricke J, Meyer-Wentrup F, Gorboulev V, Volk C, Loffing-Cueni D, Kaissling B, Bachmann S, and Koepsell H (2000) Localization of organic cation transporters OCT1 and OCT2 in rat kidney. Am J Physiol Renal Physiol 279: F679-F687.
Kekuda R, Prasad PD, Wu X, Wang H, Fei Y, Leibach FH, and Ganapathy V (1998) Cloning and functional characterization of a potential-sensitive polyspecific organic cation transporter (OCT3) most abundantly expressed in placenta. J Biol Chem 273: 15971-15979.
Kerb R, Brinkmann U, Chatskaia N, Gorbunov D, Gorboulev V, Mornhinweg E, Keil A, Eichelbaum M, and Koepsell H (2002) Identification of genetic variations of the human organic cation transporter hOCT1 and their functional consequences. Pharmacogenetics 12: 591-595.[CrossRef][Medline]
Kimura H, Takeda M, Narikawa S, Enomoto A, Ichida K, and Endou H (2002) Human organic anion transporters and human organic cation transporters mediate renal transport of prostaglandins. J Pharmacol Exp Ther 301: 293-298.
Koepsell H and Endou H (2003) The SLC22 drug transporter family. Pfluegers Arch, in press.
Koepsell H, Schmitt BM, and Gorboulev V (2003) Organic cation transporters. Rev Physiol Biochem Pharmacol 150: 36-90.[Medline]
Lazar A, Gründemann D, Berkels R, Taubert D, Zimmermann T, and Schömig E (2003) Genetic variability of the extraneuronal monoamine transporter EMT (SLC22A3). J Hum Genet 48: 226-230.[CrossRef][Medline]
Leabman MK, Huang CC, DeYoung J, Carlson EJ, Taylor TR, De La Cruz M, Johns SJ, Stryke D, Kawamoto M, Urban TJ, et al. (2003) Natural variation in human membrane transporter genes reveals evolutionary and functional constraints. Proc Natl Acad Sci USA 100: 5896-5901.
Leabman MK, Huang CC, Kawamoto M, Johns SJ, Stryke D, Ferrin TE, DeYoung J, Taylor T, Clark AG, Herskowitz I, et al. (2002) Polymorphisms in a human kidney xenobiotic transporter, OCT2, exhibit altered function. Pharmacogenetics 12: 395-405.[CrossRef][Medline]
Meyer-Wentrup F, Karbach U, Gorboulev V, Arndt P, and Koepsell H (1998) Membrane localization of the electrogenic cation transporter rOCT1 in rat liver. Biochem Biophys Res Commun 248: 673-678.[CrossRef][Medline]
Mooslehner KA and Allen ND (1999) Cloning of the mouse organic cation transporter 2 gene, Slc22a2, from an enhancer-trap transgene integration locus. Mamm Genome 10: 218-224.[CrossRef][Medline]
Motohashi H, Sakurai Y, Saito H, Masuda S, Urakami Y, Goto M, Fukatsu A, Ogawa O, and Inui K (2002) Gene expression levels and immunolocalization of organic ion transporters in the human kidney. J Am Soc Nephrol 13: 866-874.
Okuda M, Saito H, Urakami Y, Takano M, and Inui K (1996) cDNA cloning and functional expression of a novel rat kidney organic cation transporter, OCT2. Biochem Biophys Res Commun 224: 500-507.[CrossRef][Medline]
Rajan PD, Kekuda R, Chancy CD, Huang W, Ganapathy V, and Smith SB (2000) Expression of the extraneuronal monoamine transporter in RPE and neural retina. Curr Eye Res 20: 195-204.[CrossRef][Medline]
Saito S, Iida A, Sekine A, Ogawa C, Kawauchi S, Higuchi S, and Nakamura Y (2002) Catalog of 238 variations among six human genes encoding solute carriers (hSLCs) in the Japanese population. J Hum Genet 47: 576-584.[CrossRef][Medline]
Schweifer N and Barlow DP (1996) The Lx1 gene maps to mouse chromosome 17 and codes for a protein that is homologous to glucose and polyspecific transmembrane transporters. Mamm Genome 7: 735-740.[CrossRef][Medline]
Shu Y, Leabman MK, Feng B, Mangravite LM, Huang CC, Stryke D, Kawamoto M, Johns SJ, DeYoung J, Carlson E, et al. (2003) Evolutionary conservation predicts function of variants of the human organic cation transporter, OCT1. Proc Natl Acad Sci USA 100: 5902-5907.
Slitt AL, Cherrington NJ, Hartley DP, Leazer TM, and Klaassen CD (2002) Tissue distribution and renal developmental changes in rat organic cation transporter mRNA levels. Drug Metab Dispos 30: 212-219.
Sugawara-Yokoo M, Urakami Y, Koyama H, Fujikura K, Masuda S, Saito H, Naruse T, Inui K, and Takata K (2000) Differential localization of organic cation transporters rOCT1 and rOCT2 in the basolateral membrane of rat kidney proximal tubules. Histochem Cell Biol 114: 175-180.[CrossRef][Medline]
Sweet DH, Bush KT, and Nigam SK (2001) The organic anion transporter family: from physiology to ontogeny and the clinic. Am J Physiol Renal Physiol 281: F197-F205.
Sweet DH, Miller DS, and Pritchard JB (2002) Ventricular choline transport: a role for organic cation transporter 2 expressed in choroid plexus. J Biol Chem 276: 41611-41619.
Terashita S, Dresser MJ, Zhang L, Gray AT, Yost SC, and Giacomini KM (1998) Molecular cloning and functional expression of a rabbit renal organic cation transporter. Biochim Biophys Acta 1369: 1-6.[Medline]
Urakami Y, Akazawa M, Saito H, Okuda M, and Inui K (2002) cDNA cloning, functional characterization and tissue distribution of an alternatively spliced variant of organic cation transporter hOCT2 predominantly expressed in the human kidney. J Am Soc Nephrol 13: 1703-1710.
Urakami Y, Nakamura N, Takahashi K, Okuda M, Saito H, Hashimoto Y, and Inui K (1999) Gender differences in expression of organic cation transporter OCT2 in rat kidney. FEBS Lett 461: 339-342.[CrossRef][Medline]
Urakami Y, Okuda M, Masuda S, Saito H, and Inui KI (1998) Functional characteristics and membrane localization of rat multispecific organic cation transporters, OCT1 and OCT2, mediating tubular secretion of cationic drugs. J Pharmacol Exp Ther 287: 800-805.
Urakami Y, Okuda M, Saito H, and Inui K (2000) Hormonal regulation of organic cation transporter OCT2 expression in rat kidney. FEBS Lett 473: 173-176.[CrossRef][Medline]
Van Montfoort JE, Muller M, Groothuis GM, Meijer DK, Koepsell H, and Meier PJ (2001) Comparison of "type I" and "type II" organic cation transport by organic cation transporters and organic anion-transporting polypeptides. J Pharmacol Exp Ther 298: 110-115.
Verhaagh S, Schweifer N, Barlow DP, and Zwart R (1999) Cloning of the mouse and human solute carrier 22a3 (Slc22a3/SLC22A3) identifies a conserved cluster of three organic cation transporters on mouse chromosome 17 and human 6q26-q27. Genomics 55: 209-218.[CrossRef][Medline]
Wang DS, Jonker JW, Kato Y, Kusuhara H, Schinkel AH, and Sugiyama Y (2002) Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. J Pharmacol Exp Ther 302: 510-515.
Wang DS, Kusuhara H, Kato Y, Jonker JW, Schinkel AH, and Sugiyama Y (2003) Involvement of organic cation transporter 1 in lactic acidosis caused by metformin. Mol Pharmacol 63: 844-848.
Wu X, Kekuda R, Huang W, Fei Y, Leibach FH, Chen J, Conway SJ, and Ganapathy V (1998a) Identity of the organic cation transporter OCT3 as the extraneuronal monoamine transporter (uptake2) and evidence for the expression of the transporter in the brain. J Biol Chem 273: 32776-32786.
Wu X, Prasad PD, Leibach FH, and Ganapathy V (1998b) cDNA sequence, transport function and genomic organization of human OCTN2, a new member of the organic cation transporter family. Biochem Biophys Res Commun 246: 589-595.[CrossRef][Medline]
Zhang L, Dresser MJ, Chun JK, Babbitt PC, and Giacomini KM (1997a) Cloning and functional characterization of a rat renal organic cation transporter isoform (rOCT1A). J Biol Chem 272: 16548-16554.
Zhang L, Dresser MJ, Gray AT, Yost SC, Terashita S, and Giacomini KM (1997b) Cloning and functional expression of a human liver organic cation transporter. Mol Pharmacol 51: 913-921.
Zhang L, Schaner ME, and Giacomini KM (1998) Functional characterization of an organic cation transporter (hOCT1) in a transiently transfected human cell line (HeLa). J Pharmacol Exp Ther 286: 354-361.
Zhang X, Evans KK, and Wright SH (2002) Molecular cloning of rabbit organic cation transporter rbOCT2 and functional comparisons with rbOCT1. Am J Renal Physiol 283: F124-F139.
Zwart R, Sleutels F, Wutz A, Schinkel AH, and Barlow DP (2001a) Bidirectional action of the Igf2r imprint control element on upstream and downstream imprinted genes. Genes Dev 15: 2361-2366.
Zwart R, Verhaagh S, Buitelaar M, Popp-Snijders C, and Barlow DP (2001b) Impaired activity of the extraneuronal monoamine transporter system known as uptake-2 in Orct3/Slc22a3-deficient mice. Mol Cell Biol 21: 4188-4196.
This article has been cited by other articles:
|
|
 |
|
  M. Aoki, T. Terada, M. Kajiwara, K. Ogasawara, I. Ikai, O. Ogawa, T. Katsura, and K.-i. Inui Kidney-specific expression of human organic cation transporter 2 (OCT2/SLC22A2) is regulated by DNA methylation Am J Physiol Renal Physiol, July 1, 2008; 295(1): F165 - F170. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Josse, C. Aninat, D. Glaise, J. Dumont, V. Fessard, F. Morel, J.-M. Poul, C. Guguen-Guillouzo, and A. Guillouzo Long-Term Functional Stability of Human HepaRG Hepatocytes and Use for Chronic Toxicity and Genotoxicity Studies Drug Metab. Dispos., June 1, 2008; 36(6): 1111 - 1118. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Matsuzaki, T. Morisaki, W. Sugimoto, K. Yokoo, D. Sato, H. Nonoguchi, K. Tomita, T. Terada, K.-i. Inui, A. Hamada, et al. Altered Pharmacokinetics of Cationic Drugs Caused by Down-Regulation of Renal Rat Organic Cation Transporter 2 (Slc22a2) and Rat Multidrug and Toxin Extrusion 1 (Slc47a1) in Ischemia/Reperfusion-Induced Acute Kidney Injury Drug Metab. Dispos., April 1, 2008; 36(4): 649 - 654. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Hilgendorf, G. Ahlin, A. Seithel, P. Artursson, A.-L. Ungell, and J. Karlsson Expression of Thirty-six Drug Transporter Genes in Human Intestine, Liver, Kidney, and Organotypic Cell Lines Drug Metab. Dispos., August 1, 2007; 35(8): 1333 - 1340. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Chen, S. Zhang, M. Sorani, and K. M. Giacomini Transport of Paraquat by Human Organic Cation Transporters and Multidrug and Toxic Compound Extrusion Family J. Pharmacol. Exp. Ther., August 1, 2007; 322(2): 695 - 700. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-i. Asaka, T. Terada, K. Ogasawara, T. Katsura, and K.-i. Inui Characterization of the Basal Promoter Element of Human Organic Cation Transporter 2 Gene J. Pharmacol. Exp. Ther., May 1, 2007; 321(2): 684 - 689. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-J. Kang, I.-S. Song, H. J. Shin, W.-Y. Kim, C.-H. Lee, J.-C. Shim, H.-H. Zhou, S. S. Lee, and J.-G. Shin Identification and Functional Characterization of Genetic Variants of Human Organic Cation Transporters in a Korean Population Drug Metab. Dispos., April 1, 2007; 35(4): 667 - 675. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Watanabe, Y. Kato, T. Sugiura, Y. Kubo, T. Wakayama, S. Iseki, and A. Tsuji PDZ Adaptor Protein PDZK2 Stimulates Transport Activity of Organic Cation/Carnitine Transporter OCTN2 by Modulating Cell Surface Expression Drug Metab. Dispos., November 1, 2006; 34(11): 1927 - 1934. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Yonezawa, S. Masuda, S. Yokoo, T. Katsura, and K.-i. Inui Cisplatin and Oxaliplatin, but Not Carboplatin and Nedaplatin, Are Substrates for Human Organic Cation Transporters (SLC22A1-3 and Multidrug and Toxin Extrusion Family) J. Pharmacol. Exp. Ther., November 1, 2006; 319(2): 879 - 886. [Abstract] [Full Text] |
Top
Abstract
Cloning and Functional...
