Transport of drugs in the kidney by the human organic cation transporter, OCT2 and its genetic variants

University of California, San Francisco, San Francisco, California, United States
Journal of Pharmaceutical Sciences (Impact Factor: 2.59). 01/2006; 95(1):25-36. DOI: 10.1002/jps.20536
Source: PubMed


The human organic cation transporter 2 (OCT2, SLC22A2) is a multispecific transporter of organic cations, including many clinically used drugs. OCT2 is primarily responsible for the uptake of organic cations across the basolateral membrane of renal tubular epithelial cells and is considered a major transporter in the active secretion of organic cations in the kidney. Uptake of organic cations by OCT2 is driven by the inside-negative membrane potential and is pH-sensitive. Regulation of OCT2 at the transcriptional level by steroid hormones and at the protein level by various protein kinases has been described. Several human genetic variants in the coding region of OCT2 have been identified and functionally characterized, including both polymorphic and rare variants. A variety of structurally diverse compounds have been shown to interact with OCT2, including endogenous compounds, drugs, and dietary supplements.

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    • "The levels of BUN and Cr, tissue damage scores, testis and kidney weights, as well as the significant correlation between kidney or testis weight and kidney damage score all together indicate that intensity of kidney toxicity in group 1 (low dose of Mg) is higher than those in other groups. At this time, we cannot interpret any documented mechanism for this finding, but the human organic cation transporter 2 (OCT2) is responsible for the uptake of organic cations across the basolateral membrane in kidneys.[36] Moreover, OCT2 is Mg-dependent and hypomagnesemia causes upregulation of OCT2, which increases the accumulation of CP in the kidney.[3738] "
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    ABSTRACT: Cisplatin (CP) is used as the commonest drug to treat solid tumors. It is accompanied by a nephrotoxicity side effect. The main objective of this study is to investigate the protective role of magnesium (Mg) supplementation in CP-induced nephrotoxicity in a rat model. Twenty-nine Wistar rats were randomly assigned to four groups (1-4). Groups 1-3 received 20, 80, and 200 mg/kg magnesium sulfate respectively, for 10 days, but on day 3, a single dose of CP (7 mg/kg, i.p.) was also injected. Group 4 (positive control group) received the same regimen of Groups 1-3 except saline instead magnesium sulfate. One week after CP administration, blood samples were obtained and all animals were killed for kidney histopathological investigations. All CP-treated animals lost weight, and the percentage of weight loss in Group 1 (low dose Mg sulfate treated) was significantly higher compared with the positive control group (Group 4, P < 0.05). The increase in blood urea nitrogen (BUN) and creatinine (Cr) levels in serum in Group 1 were more than those in other groups (P < 0.05). No statistical differences were observed in serum magnesium, nitrite, and total protein levels among the groups. The kidney tissue damage in Groups 1-3 was not significantly different when compared with Group 4. Moreover, the kidney and testis weights in Group 1 were significantly greater than those in the positive control group (P < 0.05). Regarding the BUN and Cr levels in the serum, kidneys weight, and the histopathological study, the low dose of Mg supplementation intensifies kidney toxicity and renal dysfunction in CP-induced nephrotoxicity in the rat model. However, the protective role of Mg with moderate and high doses is not certain.
    Full-text · Article · Sep 2012 · International journal of preventive medicine
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    • "The SLC22A2-808G>T variant has been identified with an allele frequency higher than 10% in all ethnic groups [12]–[14]. It has been investigated as a contributing factor to the inter-individual variation in the disposition and distribution of substrate drugs [13]–[15]. "
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    ABSTRACT: Genetic polymorphisms of the organic cation transporter 2 (OCT2), encoded by SLC22A2, have been investigated in association with metformin disposition. A functional decrease in transport function has been shown to be associated with the OCT2 variants. Using metabolomics, our study aims at a comprehensive monitoring of primary metabolite changes in order to understand biochemical alteration associated with OCT2 polymorphisms and discovery of potential endogenous metabolites related to the genetic variation of OCT2. Using GC-TOF MS based metabolite profiling, clear clustering of samples was observed in Partial Least Square Discriminant Analysis, showing that metabolic profiles were linked to the genetic variants of OCT2. Tryptophan and uridine presented the most significant alteration in SLC22A2-808TT homozygous and the SLC22A2-808G>T heterozygous variants relative to the reference. Particularly tryptophan showed gene-dose effects of transporter activity according to OCT2 genotypes and the greatest linear association with the pharmacokinetic parameters (Cl(renal), Cl(sec), Cl/F/kg, and Vd/F/kg) of metformin. An inhibition assay demonstrated the inhibitory effect of tryptophan on the uptake of 1-methyl-4-phenyl pyrinidium in a concentration dependent manner and subsequent uptake experiment revealed differential tryptophan-uptake rate in the oocytes expressing OCT2 reference and variant (808G>T). Our results collectively indicate tryptophan can serve as one of the endogenous substrate for the OCT2 as well as a biomarker candidate indicating the variability of the transport activity of OCT2.
    Full-text · Article · May 2012 · PLoS ONE
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    • "Organic cations (OCs) consist of a class of structurally diverse endogenous compounds (e.g., biogenic amines) and xenobiotics (e.g., drugs and environmental toxins) that carry a net positive charge at physiological pH. To eliminate hydrophilic OCs from the body, mammalian cells have evolved complex OC transport systems including the classic organic cation transporters 1 to 3 (OCT1–3) from the solute carrier 22 (SLC22) family and the multidrug and toxin extrusion proteins 1 and 2 from the solute carrier 47 (SLC47) family (Koepsell and Endou, 2004; Wright and Dantzler, 2004; Otsuka et al., 2005; Fujita et al., 2006). Our laboratory recently cloned and characterized a novel polyspecific organic cation transporter, the plasma membrane monoamine transporter (PMAT) (Engel et al., 2004; Engel and Wang, 2005; Ho et al., 2011). "
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    ABSTRACT: Plasma membrane monoamine transporter (PMAT) is a polyspecific organic cation (OC) transporter that transports a variety of endogenous biogenic amines and xenobiotic cations. Previous radiotracer uptake studies showed that PMAT-mediated OC transport is sensitive to changes in membrane potential and extracellular pH, but the precise role of membrane potential and protons on PMAT-mediated OC transport is unknown. Here, we characterized the electrophysiological properties of PMAT in Xenopus laevis oocytes using a two-microelectrode voltage-clamp approach. PMAT-mediated histamine uptake is associated with inward currents under voltage-clamp conditions, and the currents increased in magnitude as the holding membrane potential became more negative. A similar effect was also observed for another cation, nicotine. Substrate-induced currents were largely independent of Na+ but showed strong dependence on membrane potential and pH of the perfusate. Detailed kinetic analysis of histamine uptake revealed that the energizing effect of membrane potentials on PMAT transport is mainly due to an augmentation of Imax with little effect on K0.5. At most holding membrane potentials, Imax at pH 6.0 is approximately 3- to 4-fold higher than that at pH 7.5, whereas K0.5 is not dependent on pH. Together, these data unequivocally demonstrate PMAT as an electrogenic transporter and establish the physiological inside-negative membrane potential as a driving force for PMAT-mediated OC transport. The important role of membrane potential and pH in modulating the transport activity of PMAT toward OCs suggests that the in vivo activity of PMAT could be regulated by pathophysiological processes that alter physiological pH or membrane potential.
    Full-text · Article · Mar 2012 · Drug metabolism and disposition: the biological fate of chemicals
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