Journal articles: 'SLC22A23'

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Engelhart, Darcy C., Jeffry C. Granados, Da Shi, Milton H. Saier Jr., Michael E. Baker, Ruben Abagyan, and Sanjay K. Nigam. "Systems Biology Analysis Reveals Eight SLC22 Transporter Subgroups, Including OATs, OCTs, and OCTNs." International Journal of Molecular Sciences 21, no. 5 (March 5, 2020): 1791. http://dx.doi.org/10.3390/ijms21051791.

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The SLC22 family of OATs, OCTs, and OCTNs is emerging as a central hub of endogenous physiology. Despite often being referred to as “drug” transporters, they facilitate the movement of metabolites and key signaling molecules. An in-depth reanalysis supports a reassignment of these proteins into eight functional subgroups, with four new subgroups arising from the previously defined OAT subclade: OATS1 (SLC22A6, SLC22A8, and SLC22A20), OATS2 (SLC22A7), OATS3 (SLC22A11, SLC22A12, and Slc22a22), and OATS4 (SLC22A9, SLC22A10, SLC22A24, and SLC22A25). We propose merging the OCTN (SLC22A4, SLC22A5, and Slc22a21) and OCT-related (SLC22A15 and SLC22A16) subclades into the OCTN/OCTN-related subgroup. Using data from GWAS, in vivo models, and in vitro assays, we developed an SLC22 transporter-metabolite network and similar subgroup networks, which suggest how multiple SLC22 transporters with mono-, oligo-, and multi-specific substrate specificity interact to regulate metabolites. Subgroup associations include: OATS1 with signaling molecules, uremic toxins, and odorants, OATS2 with cyclic nucleotides, OATS3 with uric acid, OATS4 with conjugated sex hormones, particularly etiocholanolone glucuronide, OCT with neurotransmitters, and OCTN/OCTN-related with ergothioneine and carnitine derivatives. Our data suggest that the SLC22 family can work among itself, as well as with other ADME genes, to optimize levels of numerous metabolites and signaling molecules, involved in organ crosstalk and inter-organismal communication, as proposed by the remote sensing and signaling theory.

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Moss, Darren M., Neill J. Liptrott, Paul Curley, Marco Siccardi, David J. Back, and Andrew Owen. "Rilpivirine Inhibits Drug Transporters ABCB1, SLC22A1, and SLC22A2In Vitro." Antimicrobial Agents and Chemotherapy 57, no. 11 (September 3, 2013): 5612–18. http://dx.doi.org/10.1128/aac.01421-13.

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ABSTRACTRilpivirine is a nonnucleoside reverse transcriptase inhibitor approved for treatment of HIV-1 infection in antiretroviral-naive adult patients. Potential interactions with drug transporters have not been fully investigated. Transport by and inhibition of drug transporters by rilpivirine were analyzed to further understand the mechanisms governing rilpivirine exposure and determine the potential for transporter-mediated drug-drug interactions. The ability of rilpivirine to inhibit or be transported by ABCB1 was determined using ABCB1-overexpressing CEMVBL100cells and Caco-2 cell monolayers. TheXenopus laevisoocyte heterologous protein expression system was used to clarify if rilpivirine was either transported by or inhibited the function of influx transporters SLCO1A2, SLCO1B1, SLCO1B3, SLC22A2, SLC22A6, and SLC22A8. The ability of rilpivirine to inhibit or be transported by SLC22A1 was determined using SLC22A1-expressing KCL22 cells. Rilpivirine showed higher accumulation in SLC22A1-overexpressing KCL22 cells than control cells (27% increase,P= 0.03) and inhibited the functionality of SLC22A1 and SLC22A2 transport with 50% inhibitory concentrations (IC50s) of 28.5 μM and 5.13 μM, respectively. Inhibition of ABCB1-mediated digoxin transport was determined for rilpivirine, which inhibited digoxin transport in the B-to-A direction with an IC50of 4.48 μM. The maximum rilpivirine concentration in plasma in patients following a standard 25-mg dosing regimen is around 0.43 μM, lower than that necessary to substantially inhibit ABCB1, SLC22A1, or SLC22A2in vitro. However, these data indicate that SLC22A1 may contribute to variability in rilpivirine exposure and that interactions of rilpivirine with substrates of SLC22A1, SLC22A2, or ABCB1 may be possible.

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Kang, Weiting, Meng Zhang, Qiang Wang, Da Gu, Zhilong Huang, Hanbo Wang, Yuzhu Xiang, Qinghua Xia, Zilian Cui, and Xunbo Jin. "The SLC Family Are Candidate Diagnostic and Prognostic Biomarkers in Clear Cell Renal Cell Carcinoma." BioMed Research International 2020 (May 2, 2020): 1–17. http://dx.doi.org/10.1155/2020/1932948.

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Clear cell renal cell carcinoma (ccRCC) is the most common lethal subtype of renal cancer, and changes in tumor metabolism play a key role in its development. Solute carriers (SLCs) are important in the transport of small molecules in humans, and defects in SLC transporters can lead to serious diseases. The expression patterns and prognostic values of SLC family transporters in the development of ccRCC are still unclear. The current study analyzed the expression levels of SLC family members and their correlation with prognosis in ccRCC patients with data from Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), The Cancer Genome Atlas (TCGA), cBioPortal, the Human Protein Atlas (HPA), the International Cancer Genome Consortium (ICGC), and the Gene Expression Omnibus (GEO). We found that the mRNA expression levels of SLC22A6, SLC22A7, SLC22A13, SLC25A4, SLC34A1, and SLC44A4 were significantly lower in ccRCC tissues than in normal tissues and the protein expression levels of SLC22A6, SLC22A7, SLC22A13, and SLC34A1 were also significantly lower. Except for SLC22A7, the expression levels of SLC22A6, SLC22A13, SLC25A4, SLC34A1, and SLC44A4 were correlated with the clinical stage of ccRCC patients. The lower the expression levels of SLC22A6, SLC22A13, SLC25A4, SLC34A1, and SLC44A4 were, the later the clinical stage of ccRCC patients was. Further experiments revealed that the expression levels of SLC22A6, SLC22A7, SLC22A13, SLC25A4, SLC34A1, and SLC44A4 were significantly associated with overall survival (OS) and disease-free survival (DFS) in ccRCC patients. High SLC22A6, SLC22A7, SLC22A13, SLC25A4, SLC34A1, and SLC44A4 expression predicted improved OS and DFS. Finally, GSE53757 and ICGC were used to revalidate the differential expression and clinical prognostic value. This study suggests that SLC22A6, SLC22A7, SLC22A13, SLC25A4, SLC34A1, and SLC44A4 may be potential targets for the clinical diagnosis, prognosis, and treatment of ccRCC patients.

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Lapczuk-Romanska, Joanna, Diana Busch, Ewa Gieruszczak, Agnieszka Drozdzik, Katarzyna Piotrowska, Robert Kowalczyk, Stefan Oswald, and Marek Drozdzik. "Membrane Transporters in Human Parotid Gland-Targeted Proteomics Approach." International Journal of Molecular Sciences 20, no. 19 (September 28, 2019): 4825. http://dx.doi.org/10.3390/ijms20194825.

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Salivary glands provide secretory functions, including secretion of xenobiotics and among them drugs. However, there is no published information about protein abundance of drug transporters measured using reliable protein quantification methods. Therefore, mRNA expression and absolute protein content of clinically relevant ABC (n = 6) and SLC (n = 15) family member transporters in the human parotid gland, using the qRT-PCR and liquid chromatography‒tandem mass spectrometry (LC−MS/MS) method, were studied. The abundance of nearly all measured proteins ranged between 0.04 and 0.45 pmol/mg (OCT3 > MRP1 > PEPT2 > MRP4 > MATE1 > BCRP). mRNAs of ABCB1, ABCC2, ABCC3, SLC10A1, SLC10A2, SLC22A1, SLC22A5, SLC22A6, SLC22A7, SLC22A8, SLCO1A2, SLCO1B1, SLCO1B3 and SLCO2B1 were not detected. The present study provides, for the first time, information about the protein abundance of membrane transporters in the human parotid gland, which could further be used to define salivary bidirectional transport (absorption and secretion) mechanisms of endogenous compounds and xenobiotics.

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Bennett, Katie M., Jun Liu, Courtney Hoelting, and James Stoll. "Expression and analysis of two novel rat organic cation transporter homologs, SLC22A17 and SLC22A23." Molecular and Cellular Biochemistry 352, no. 1-2 (February 27, 2011): 143–54. http://dx.doi.org/10.1007/s11010-011-0748-y.

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AL-Eitan, Laith, Basima Almomani, Ahmad Nassar, Barakat Elsaqa, and Nesreen Saadeh. "Metformin Pharmacogenetics: Effects of SLC22A1, SLC22A2, and SLC22A3 Polymorphisms on Glycemic Control and HbA1c Levels." Journal of Personalized Medicine 9, no. 1 (March 25, 2019): 17. http://dx.doi.org/10.3390/jpm9010017.

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Type 2 diabetes mellitus (T2DM) constitutes a major portion of Jordan’s disease burden, and incidence rates are rising at a rapid rate. Due to variability in the drug’s response between ethnic groups, it is imperative that the pharmacogenetics of metformin be investigated in the Jordanian population. The objective of this study was to investigate the relationship between twenty-one single nucleotide polymorphisms (SNPs) in the SLC22A1, SLC22A2, and SLC22A3 genes and their effects on metformin pharmacogenetics in Jordanian patients diagnosed with type 2 diabetes mellitus. Blood samples were collected from 212 Jordanian diabetics who fulfilled the inclusion criteria, which were then used in SNP genotyping and determination of HbA1c levels. The rs12194182 SNP in the SLC22A3 gene was found to have a significant association (p < 0.05) with lower mean HbA1c levels, and this association more pronounced in patients with the CC genotype (i.e., p-value was significant before correcting for multiple testing). Moreover, the multinomial logistic regression analysis showed that SNP genotypes within the SLC22A1, SLC22A2, and SLC22A3 genes, body mass index (BMI) and age of diagnosis were significantly associated with glycemic control (p < 0.05). The results of this study can be used to predict response to metformin and other classes of T2DM drugs, making treatment more individualized and resulting in better clinical outcomes.

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Gottier Nwafor, Janine, Marta Nowik, Naohiko Anzai, Hitoshi Endou, and Carsten A. Wagner. "Metabolic Acidosis Alters Expression of Slc22 Transporters in Mouse Kidney." Kidney and Blood Pressure Research 45, no. 2 (2020): 263–74. http://dx.doi.org/10.1159/000506052.

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Introduction: The kidneys play a central role in eliminating metabolic waste products and drugs through transporter-mediated excretion along the proximal tubule. This task is mostly achieved through a variety of transporters from the solute carrier family 22 (SLC22) family of organic cation and anion transporters. Metabolic acidosis modulates metabolic and renal functions and also affects the clearance of metabolites and drugs from the body. We had previously shown that induction of metabolic acidosis in mice alters a large set of transcripts, among them also many transporters including transporters from the Slc22 family. Objective: Here we further investigated the impact of acidosis on Slc22 family members. Methods: Metabolic acidosis was induced for 2 or 7 days with NH4Cl, some animals also received the uricase inhibitor oxonic acid for comparison. Expression of transporters was studied by qPCR and immunoblotting. Results: NH4Cl induced no significant changes in plasma or urine uric acid levels but caused downregulation of Slc22a1 (Oct1), Slc22a6 (Oat1), Slc22a19 (Oat5), and Slc22a12 (Urat1) at mRNA level. In contrast, Slc22a4 mRNA (Octn1) was upregulated. On protein level, NH4Cl increased Octn1 (after 7 days) and Urat1 (after 2 days) abundance and decreased Oat1 (after 2 days) and Urat1 (after 7 days). Oxonic acid had no impact on protein abundance of any of the transporters tested. Conclusion: In summary, metabolic acidosis alters expression of several transporters involved in renal excretion of metabolic waste products and drugs. This may have implications for drug kinetics and clearance of waste metabolites.

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Cheong, Hyun Sub, Hae Deun Kim, Han Sung Na, Ji On Kim, Lyoung Hyo Kim, Seung Hee Kim, Joon Seol Bae, Myeon Woo Chung, and Hyoung Doo Shin. "Screening of genetic variations of SLC15A2, SLC22A1, SLC22A2 and SLC22A6 genes." Journal of Human Genetics 56, no. 9 (July 28, 2011): 666–70. http://dx.doi.org/10.1038/jhg.2011.77.

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Engelhart, Darcy C., Priti Azad, Suwayda Ali, Jeffry C. Granados, Gabriel G. Haddad, and Sanjay K. Nigam. "Drosophila SLC22 Orthologs Related to OATs, OCTs, and OCTNs Regulate Development and Responsiveness to Oxidative Stress." International Journal of Molecular Sciences 21, no. 6 (March 15, 2020): 2002. http://dx.doi.org/10.3390/ijms21062002.

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The SLC22 family of transporters is widely expressed, evolutionarily conserved, and plays a major role in regulating homeostasis by transporting small organic molecules such as metabolites, signaling molecules, and antioxidants. Analysis of transporters in fruit flies provides a simple yet orthologous platform to study the endogenous function of drug transporters in vivo. Evolutionary analysis of Drosophila melanogaster putative SLC22 orthologs reveals that, while many of the 25 SLC22 fruit fly orthologs do not fall within previously established SLC22 subclades, at least four members appear orthologous to mammalian SLC22 members (SLC22A16:CG6356, SLC22A15:CG7458, CG7442 and SLC22A18:CG3168). We functionally evaluated the role of SLC22 transporters in Drosophila melanogaster by knocking down 14 of these genes. Three putative SLC22 ortholog knockdowns—CG3168, CG6356, and CG7442/SLC22A—did not undergo eclosion and were lethal at the pupa stage, indicating the developmental importance of these genes. Additionally, knocking down four SLC22 members increased resistance to oxidative stress via paraquat testing (CG4630: p < 0.05, CG6006: p < 0.05, CG6126: p < 0.01 and CG16727: p < 0.05). Consistent with recent evidence that SLC22 is central to a Remote Sensing and Signaling Network (RSSN) involved in signaling and metabolism, these phenotypes support a key role for SLC22 in handling reactive oxygen species.

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Tamai, Ikumi. "Pharmacological and pathophysiological roles of carnitine/organic cation transporters (OCTNs: SLC22A4, SLC22A5 and Slc22a21)." Biopharmaceutics & Drug Disposition 34, no. 1 (October 14, 2012): 29–44. http://dx.doi.org/10.1002/bdd.1816.

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Wu, Wei, Michael E. Baker, Satish A. Eraly, Kevin T. Bush, and Sanjay K. Nigam. "Analysis of a large cluster of SLC22 transporter genes, including novel USTs, reveals species-specific amplification of subsets of family members." Physiological Genomics 38, no. 2 (July 2009): 116–24. http://dx.doi.org/10.1152/physiolgenomics.90309.2008.

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When the organic anion transporter Oat1 was first identified as NKT (Lopez-Nieto CE, You G, Bush KT, Barros EJ, Beier DR, Nigam SK. J Biol Chem 272: 6471–6478, 1997), it was argued that it, together with Oct1, may be part of a larger subfamily (now known as SLC22) involved in organic ion and xenobiotic transport. The least studied among SLC22 transporters are the so-called unknown substrate transporters ( USTs). Here, five novel genes located in a cluster on mouse chromosome 19, immediately between Slc22a8 ( Oat3)/ Slc22a6 ( Oat1) and Slc22a19 ( Oat5), were identified as homologs of human USTs. These genes display preferential expression in liver and kidney, and one gene, AB056422, has several splicing variants with differential tissue expression and embryonic expression. Along with Slc22a6, Slc22a8, and Slc22a19, these Usts define the largest known cluster of mammalian Slc22 genes. Given the established functions of Oats, these genes may also be involved in organic anion transport. Usts have characteristic motifs and share a signature residue in the possible active site of transmembrane domain 7, a conserved, positively charged, amino acid, Arg356, possibly a site for interaction with organic anions. In certain species, Oat1 and Oat3 appeared to be highly conserved, whereas the Ust part of this cluster appeared to undergo repeated species-specific amplification, suggesting strong environmental selection pressure, and perhaps providing an explanation for copy number variation in the human locus. One Ust amplification in mouse appears to be recent. This cluster may be coordinately regulated and under selective pressure in a species-specific manner.

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Zazuli, Zulfan, Naut J. C. B. Duin, Katja Jansen, Susanne J. H. Vijverberg, Anke H. Maitland-van der Zee, and Rosalinde Masereeuw. "The Impact of Genetic Polymorphisms in Organic Cation Transporters on Renal Drug Disposition." International Journal of Molecular Sciences 21, no. 18 (September 10, 2020): 6627. http://dx.doi.org/10.3390/ijms21186627.

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A considerable number of drugs and/or their metabolites are excreted by the kidneys through glomerular filtration and active renal tubule secretion via transporter proteins. Uptake transporters in the proximal tubule are part of the solute carrier (SLC) superfamily, and include the organic cation transporters (OCTs). Several studies have shown that specific genetic polymorphisms in OCTs alter drug disposition and may lead to nephrotoxicity. Multiple single nucleotide polymorphisms (SNPs) have been reported for the OCT genes (SLC22A1, SLC22A2 and SLC22A3), which can influence the proteins’ structure and expression levels and affect their transport function. A gain-in-function mutation may lead to accumulation of drugs in renal proximal tubule cells, eventually leading to nephrotoxicity. This review illustrates the impact of genetic polymorphisms in OCTs on renal drug disposition and kidney injury, the clinical significances and how to personalize therapies to minimize the risk of drug toxicity.

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Mulgaonkar, Aditi, Jürgen Venitz, Dirk Gründemann, and Douglas H. Sweet. "Human Organic Cation Transporters 1 (SLC22A1), 2 (SLC22A2), and 3 (SLC22A3) as Disposition Pathways for Fluoroquinolone Antimicrobials." Antimicrobial Agents and Chemotherapy 57, no. 6 (April 1, 2013): 2705–11. http://dx.doi.org/10.1128/aac.02289-12.

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ABSTRACTFluoroquinolones (FQs) are important antimicrobials that exhibit activity against a wide range of bacterial pathogens and excellent tissue permeation. They exist as charged molecules in biological fluids, and thus, their disposition depends heavily on active transport and facilitative diffusion. A recent review of the clinical literature indicated that tubular secretion and reabsorption are major determinants of their half-life in plasma, efficacy, and drug-drug interactions. In particular, reportedin vivointeractions between FQs and cationic drugs affecting renal clearance implicated organic cation transporters (OCTs). In this study, 13 FQs, ciprofloxacin, enoxacin, fleroxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, pefloxacin, prulifloxacin, rufloxacin, and sparfloxacin, were screened for their ability to inhibit transport activity of human OCT1 (hOCT1) (SLC22A1), hOCT2 (SLC22A2), and hOCT3 (SLC22A3). All, with the exception of enoxacin, significantly inhibited hOCT1-mediated uptake under initial test conditions. None of the FQs inhibited hOCT2, and only moxifloxacin inhibited hOCT3 (∼30%), even at a 1,000-fold excess. Gatifloxacin, moxifloxacin, prulifloxacin, and sparfloxacin were determined to be competitive inhibitors of hOCT1. Inhibition constants (Ki) were estimated to be 250 ± 18 μM, 161 ± 19 μM, 136 ± 33 μM, and 94 ± 8 μM, respectively. Moxifloxacin competitively inhibited hOCT3-mediated uptake, with aKivalue of 1,598 ± 146 μM. Despite expression in enterocytes (luminal), hepatocytes (sinusoidal), and proximal tubule cells (basolateral), hOCT3 does not appear to contribute significantly to FQ disposition. However, hOCT1 in the sinusoidal membrane of hepatocytes, and potentially the basolateral membrane of proximal tubule cells, is likely to play a role in the disposition of these antimicrobial agents.

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Serrano León, Alejandra, Mandana Amir Shaghaghi, Natalia Yurkova, Charles N. Bernstein, Hani El-Gabalawy, and Peter Eck. "Single-nucleotide polymorphisms in SLC22A23 are associated with ulcerative colitis in a Canadian white cohort." American Journal of Clinical Nutrition 100, no. 1 (April 16, 2014): 289–94. http://dx.doi.org/10.3945/ajcn.113.080549.

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Phate, Sagar D., Bharti R. Daswani, Deepika N. Mishra, and Kedar S. Joshi. "Genetic analysis of SLC47A1, SLC22A1, SLC22A2, ATM gene polymorphisms among diabetics in an Indian population." International Journal of Basic & Clinical Pharmacology 9, no. 6 (May 21, 2020): 891. http://dx.doi.org/10.18203/2319-2003.ijbcp20202189.

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Background: Metformin is a first-line therapy for type 2 diabetes mellitus. However, the glycaemic response to metformin is likely to be affected by polymorphisms of transporter genes. Therefore, the study was done with the aim to assess demographic distribution of transporter genotypes involved in disposition and action of metformin.Methods: This cross-sectional, observational, single centre, clinical study was conducted in 80 diabetic patients recruited from medicine OPD. Descriptive analysis was done for distribution of the four transporter genotypes viz. SLC47A1 (rs2289669), ATM (rs11212617), SLC22A2 (rs316019) and SLC22A1 (rs622342). Genotyping was determined by DNA extraction, agarose gel electrophoresis, estimation of DNA concentration, polymerase chain reaction, DNA sequencing, sequencing analysis.Results: Transporter genotype analysis showed that for SLC47A1 (rs2289669) transporter, 31.25% and 26.25% were homozygous for AA and GG allele respectively, while 42.5% were heterozygous (AG). For ATM (rs11212617), SLC22A2 (rs316019) and SLC22A1 (rs622342) transporter, 45% and 10%, 1.25% and 80%, 58.75% and 7.50% were homozygous for AA and CC allele respectively; while 45%, 18.75%, 33.75% were heterozygous (AC) respectively. Interethnic differences in the genotype and allele frequencies of SLC22A1 (rs622342) and ATM (rs11212617) gene polymorphism were observed when compared with other major populations.Conclusions: In the genotypic distribution of four transporter genotype study showed that there was an ethnic variation in allelic distribution of allele A and C of ATM (rs11212617) and SLC22A1 (rs622342) while AA genotype of SLC22A2 (rs316019) was rare genotype and allele ‘A’ was major allele found in our study. The study data observed would justify further pharmacogenetic studies to evaluate the role of gene polymorphism in the therapeutic efficacy of metformin.

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Duga, Balázs, Márta Czakó, Katalin Komlósi, Kinga Hadzsiev, Katalin Sümegi, Péter Kisfali, Márton Melegh, and Béla Melegh. "Attention deficit hyperactivity disorder analyzed with array comparative genome hybridization method. Case report." Orvosi Hetilap 155, no. 40 (October 2014): 1598–601. http://dx.doi.org/10.1556/oh.2014.30006.

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One of the most common psychiatric disorders during childhood is attention deficit hyperactivity disorder, which affects 5-6% of children worldwide. Symptoms include attention deficit, hyperactivity, forgetfulness and weak impulse control. The exact mechanism behind the development of the disease is unknown. However, current data suggest that a strong genetic background is responsible, which explains the frequent occurrence within a family. Literature data show that copy number variations are very common in patients with attention deficit hyperactivity disorder. The authors present a patient with attention deficit hyperactivity disorder who proved to have two approximately 400 kb heterozygous microduplications at 6p25.2 and 15q13.3 chromosomal regions detected by comparative genomic hybridization methods. Both duplications affect genes (6p25.2: SLC22A23; 15q13.3: CHRNA7) which may play a role in the development of attention deficit hyperactivity disorder. This case serves as an example of the wide spectrum of indication of the array comparative genome hybridization method. Orv. Hetil., 2014, 155(40), 1598–1601.

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Hu, Dong Gui, Peter I. Mackenzie, Pramod C. Nair, Ross A. McKinnon, and Robyn Meech. "The Expression Profiles of ADME Genes in Human Cancers and Their Associations with Clinical Outcomes." Cancers 12, no. 11 (November 13, 2020): 3369. http://dx.doi.org/10.3390/cancers12113369.

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ADME genes are a group of genes that are involved in drug absorption, distribution, metabolism, and excretion (ADME). The expression profiles of ADME genes within tumours is proposed to impact on cancer patient survival; however, this has not been systematically examined. In this study, our comprehensive analyses of pan-cancer datasets from the Cancer Genome Atlas (TCGA) revealed differential intratumoral expression profiles for ADME genes in 21 different cancer types. Most genes also showed high interindividual variability within cancer-specific patient cohorts. Using Kaplan-Meier plots and logrank tests, we showed that intratumoral expression levels of twenty of the thirty-two core ADME genes were associated with overall survival (OS) in these cancers. Of these genes, five showed significant association with unfavourable OS in three cancers, including SKCM (ABCC2, GSTP1), KIRC (CYP2D6, CYP2E1), PAAD (UGT2B7); sixteen showed significant associations with favourable OS in twelve cancers, including BLCA (UGT2B15), BRCA (CYP2D6), COAD (NAT1), HNSC (ABCB1), KIRC (ABCG2, CYP3A4, SLC22A2, SLC22A6), KIRP (SLC22A2), LIHC (CYP2C19, CYP2C8, CYP2C9, CYP3A5, SLC22A1), LUAD (SLC15A2), LUSC (UGT1A1), PAAD (ABCB1), SARC (ABCB1), and SKCM (ABCB1, DYPD). Overall, these data provide compelling evidence supporting ADME genes as prognostic biomarkers and potential therapeutic targets. We propose that intratumoral expression of ADME genes may impact cancer patient survival by multiple mechanisms that can include metabolizing/transporting anticancer drugs, activating anticancer drugs, and metabolizing/transporting a variety of endogenous molecules involved in metabolically fuelling cancer cells and/or controlling pro-growth signalling pathways.

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Bourdet, David L., John B. Pritchard, and Dhiren R. Thakker. "Differential Substrate and Inhibitory Activities of Ranitidine and Famotidine toward Human Organic Cation Transporter 1 (hOCT1; SLC22A1), hOCT2 (SLC22A2), and hOCT3 (SLC22A3)." Journal of Pharmacology and Experimental Therapeutics 315, no. 3 (September 1, 2005): 1288–97. http://dx.doi.org/10.1124/jpet.105.091223.

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Yang, Jian, Maria Kalogerou, John Gallacher, Julian R. Sampson, and Ming Hong Shen. "Renal tumours in a Tsc1+/– mouse model show epigenetic suppression of organic cation transporters Slc22a1, Slc22a2 and Slc22a3, and do not respond to metformin." European Journal of Cancer 49, no. 6 (April 2013): 1479–90. http://dx.doi.org/10.1016/j.ejca.2012.10.027.

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Youngblood, Geri L., and Douglas H. Sweet. "Identification and functional assessment of the novel murine organic anion transporter Oat5 (Slc22a19) expressed in kidney." American Journal of Physiology-Renal Physiology 287, no. 2 (August 2004): F236—F244. http://dx.doi.org/10.1152/ajprenal.00012.2004.

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An uncharacterized murine cDNA clone was identified and, through sequence, phylogenetic, and functional analysis, determined to encode the newest member of the organic anion transporter family, organic anion transporter 5 (Oat5; Slc22a19). The Oat5 cDNA clone contained an insert 1,964 bp in length with a predicted open reading frame (from bp 84 to bp 1,739) coding for a peptide 551 amino acids long. Slc22a19 was localized to mouse chromosome 19 near the genes encoding Oat1 ( Slc22a6) and Oat3 ( Slc22a8). Northern blot analysis revealed Oat5 is highly expressed in the kidney of adult mice and rats. No sexual dimorphism in renal or hepatic expression of Oat5 was observed. Unlike Oat1–3, Oat5 expression was not detected in the choroid plexus of either mice or rats. Murine Oat5-expressing Xenopus laevis oocytes supported increased accumulation of the mycotoxin ochratoxin A, compared with water-injected control oocytes. This uptake was significantly inhibited by probenecid and the organic anions 2,4-dichlorophenoxyacetic acid, salicylate, and estrone sulfate but not by para-aminohippurate or urate. Transport of ochratoxin A by murine Oat5 was saturable, with an estimated Km of 2.0 ± 0.45 μM. Oat5-mediated transport was neither cis-inhibited nor trans-stimulated by the dicarboxylate glutarate. Uptake was also completely unaffected by short-circuiting of the membrane potential. Thus the motive forces behind Oat5 function, which provide insight into its membrane localization, need to be further resolved. These data demonstrate for the first time that this newly identified gene encodes a protein that functions as an organic anion transporter.

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Wang, Li, and Douglas H. Sweet. "Potential for food–drug interactions by dietary phenolic acids on human organic anion transporters 1 (SLC22A6), 3 (SLC22A8), and 4 (SLC22A11)." Biochemical Pharmacology 84, no. 8 (October 2012): 1088–95. http://dx.doi.org/10.1016/j.bcp.2012.07.027.

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Lee, Wing-Kee, Markus Reichold, Bayram Edemir, Giuliano Ciarimboli, Richard Warth, Hermann Koepsell, and Frank Thévenod. "Organic cation transporters OCT1, 2, and 3 mediate high-affinity transport of the mutagenic vital dye ethidium in the kidney proximal tubule." American Journal of Physiology-Renal Physiology 296, no. 6 (June 2009): F1504—F1513. http://dx.doi.org/10.1152/ajprenal.90754.2008.

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The positively charged fluorescent dyes ethidium (Et+) and propidium (Pr2+) are widely used as DNA and necrosis markers. Et+is cytotoxic and mutagenic. The polyspecific organic cation transporters OCT1 (SLC22A1), OCT2 (SLC22A2), and OCT3 (SLC22A3) mediate electrogenic facilitated diffusion of small (≤500 Da) organic cations with broad specificities. In humans, OCT2 mediates basolateral uptake by kidney proximal tubules (PT), whereas in rodents OCT1/2 are involved. In mouse kidney, perfused Et+accumulated predominantly in the S2/S3 segments of the PT, but not Pr2+. In cells stably overexpressing human OCTs (hOCTs), Et+uptake was observed with Kmvalues of 0.8 ± 0.2 μM (hOCT1), 1.7 ± 0.5 μM (hOCT2), and 2.0 ± 0.5 μM (hOCT3), whereas Pr2+was not transported. Accumulation of Et+was inhibited by OCT substrates quinine, 3-methyl-4-phenylpyridinium (MPP+), cimetidine, and tetraethylammonium (TEA+). For hOCT1 and hOCT2, the IC50values for MPP+, TEA+, and cimetidine were higher than for inhibition of previously tested transported substrates. For hOCT2, the inhibition of Et+uptake by MPP+and cimetidine was shown to be competitive. Et+also inhibited transport of 0.1 μM [3H]MPP+by all hOCT isoforms with IC50values between 0.4 and 1.3 μM, and the inhibition of hOCT1-mediated uptake of MPP+by Et+was competitive. In Oct1/2−/−mice, Et+uptake in the PT was almost abolished. The data demonstrate that Et+is taken up avidly by the PT, which is mediated by OCT1 and/or OCT2. Considering the high affinity of OCTs for Et+and their strong expression in various organs, strict safety guidelines for Et+handling should be reinforced.

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Wang, Li, and Douglas H. Sweet. "Interaction of Natural Dietary and Herbal Anionic Compounds and Flavonoids with Human Organic Anion Transporters 1 (SLC22A6), 3 (SLC22A8), and 4 (SLC22A11)." Evidence-Based Complementary and Alternative Medicine 2013 (2013): 1–7. http://dx.doi.org/10.1155/2013/612527.

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Active components of complementary/alternative medicines and natural supplements are often anionic compounds and flavonoids. As such, organic anion transporters (OATs) may play a key role in their pharmacokinetic and pharmacological profiles, and represent sites for adverse drug-drug interactions. Therefore, we assessed the inhibitory effects of nine natural products, including flavonoids (catechin and epicatechin), chlorogenic acids (1,3- and 1,5-dicaffeoylquinic acid), phenolic acids (ginkgolic acids (13 : 0), (15 : 1), and (17 : 1)), and the organic acids ursolic acid and 18β-glycyrrhetinic acid, on the transport activity of the human OATs, hOAT1 (SLC22A6), hOAT3 (SLC22A8), and hOAT4 (SLC22A11). Four compounds, 1,3- and 1,5-dicaffeoylquinic acid, ginkgolic acid (17 : 1), and 18β-glycyrrhetinic acid, significantly inhibited hOAT1-mediated transport (50 μM inhibitor versus 1 μM substrate). Five compounds, 1,3- and 1,5-dicaffeoylquinic acid, ginkgolic acids (15 : 1) and (17 : 1), and epicatechin, significantly inhibited hOAT3 transport under similar conditions. Only catechin inhibited hOAT4. Dose-dependency studies were conducted for 1,3-dicaffeoylquinic acid and 18β-glycyrrhetinic acid on hOAT1, and IC50values were estimated as 1.2 ± 0.4 μM and 2.7 ± 0.2 μM, respectively. These data suggest that 1,3-dicaffeoylquinic acid and 18β-glycyrrhetinic acid may cause significant hOAT1-mediated DDIsin vivo; potential should be considered for safety issues during use and in future drug development.

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Vassileva, Vessela, Marta Braga, Chris Barnes, Justyna Przystal, Ali Ashek, Louis Allott, Diana Brickute, et al. "Effective Detection and Monitoring of Glioma Using [18F]FPIA PET Imaging." Biomedicines 9, no. 7 (July 13, 2021): 811. http://dx.doi.org/10.3390/biomedicines9070811.

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Background: Reprogrammed cellular metabolism is a cancer hallmark. In addition to increased glycolysis, the oxidation of acetate in the citric acid cycle is another common metabolic phenotype. We have recently developed a novel fluorine-18-labelled trimethylacetate-based radiotracer, [18F]fluoro-pivalic acid ([18F]FPIA), for imaging the transcellular flux of short-chain fatty acids, and investigated whether this radiotracer can be used for the detection of glioma growth. Methods: We evaluated the potential of [18F]FPIA PET to monitor tumor growth in orthotopic patient-derived (HSJD-GBM-001) and cell line-derived (U87, LN229) glioma xenografts, and also included [18F]FDG PET for comparison. We assessed proliferation (Ki-67) and the expression of lipid metabolism and transport proteins (CPT1, SLC22A2, SLC22A5, SLC25A20) by immunohistochemistry, along with etomoxir treatment to provide insights into [18F]FPIA uptake. Results: Longitudinal PET imaging showed gradual increase in [18F]FPIA uptake in orthotopic glioma models with disease progression (p < 0.0001), and high tumor-to-brain contrast compared to [18F]FDG (p < 0.0001). [18F]FPIA uptake correlated positively with Ki-67 (p < 0.01), SLC22A5 (p < 0.001) and SLC25A20 (p = 0.001), and negatively with CPT1 (p < 0.01) and SLC22A2 (p < 0.01). Etomoxir reduced [18F]FPIA uptake, which correlated with decreased Ki-67 (p < 0.05). Conclusions: Our findings support the use of [18F]FPIA PET for the detection and longitudinal monitoring of glioma, showing a positive correlation with tumor proliferation, and suggest transcellular flux-mediated radiotracer uptake.

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Sleutels, F. "Imprinted silencing of Slc22a2 and Slc22a3 does not need transcriptional overlap between Igf2r and Air." EMBO Journal 22, no. 14 (July 15, 2003): 3696–704. http://dx.doi.org/10.1093/emboj/cdg341.

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Wang, Li, and Douglas H. Sweet. "Competitive Inhibition of Human Organic Anion Transporters 1 (SLC22A6), 3 (SLC22A8) and 4 (SLC22A11) by Major Components of the Medicinal Herb Salvia miltiorrhiza (Danshen)." Drug Metabolism and Pharmacokinetics 28, no. 3 (2013): 220–28. http://dx.doi.org/10.2133/dmpk.dmpk-12-rg-116.

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Magyari, Lili, and Béla Melegh. "Susceptibility genetic variants in Hungarian morbus Crohn and ulcerative colitis patients." Orvosi Hetilap 150, no. 2 (January 1, 2009): 81–88. http://dx.doi.org/10.1556/oh.2009.28445.

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Gyulladásos bélbetegségekre (Crohn-betegség, colitis ulcerosa) hajlamosító gének vizsgálatát végeztük magyar populációban, ezek a CARD15 gén R702W, G908R, 1007finsC variánsai, az SLC22A4 gén C1672T és az SLC22A5 G-207C variánsai, valamint az általuk meghatározott TC haplotípus, a CTLA4 gén A+49G eltérése és az IL23R gén rs10889677 C/A, rs2201841 T/C, rs1884444 G/T variánsai. Vizsgálataink során 201 felnőtt Crohn-beteg, 241 felnőtt colitis ulcerosás, valamint 19 gyermek Crohn-beteget analizáltunk. Kontrollnak 235 felnőttől és 49 gyermektől vettünk vért. A genotipizálás során PCR/RFLP módszert és direkt szekvenálást alkalmaztunk. Eredményeink alapján kijelenthetjük, hogy a CARD15 gén mutációi közül felnőttekben az 1007finsC, míg gyermekekben az 1007finsC és a G908R variáns is hajlamosít Crohn-betegség kialakulására. Az SLC22A4 és SLC22A5 gének által meghatározott TC haplotípus esetén nem találtunk szignifikáns különbséget a betegcsoportok kontrollokkal való összevetése során. A CTLA4 gén A+49G variánsa nem bizonyult hajlamosító tényezőnek gyulladásos bélbetegségekre. Az IL23R gén esetén az rs10889677 C/A és az rs2201841 T/C jelent kockázati tényezőt Crohn-betegség kialakulására. Megállapíthatjuk, hogy különböző populációktól függ, hogy az adott genetikai variánsok hajlamosítanak-e az adott populációban a gyulladásos bélbetegségek valamelyikének kialakulására.

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Breljak, Davorka, Marija Ljubojević, Yohannes Hagos, Vedran Micek, Daniela Balen Eror, Ivana Vrhovac Madunić, Hrvoje Brzica, et al. "Distribution of organic anion transporters NaDC3 and OAT1-3 along the human nephron." American Journal of Physiology-Renal Physiology 311, no. 1 (July 1, 2016): F227—F238. http://dx.doi.org/10.1152/ajprenal.00113.2016.

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The initial step in renal secretion of organic anions (OAs) is mediated by transporters in the basolateral membrane (BLM). Contributors to this process are primary active Na+-K+-ATPase (EC 3.6.3.9), secondary active Na+-dicarboxylate cotransporter 3 (NaDC3/SLC13A3), and tertiary active OA transporters (OATs) OAT1/SLC22A6, OAT2/SLC22A7, and OAT3/SLC22A8. In human kidneys, we analyzed the localization of these transporters by immunochemical methods in tissue cryosections and isolated membranes. The specificity of antibodies was validated with human embryonic kidney-293 cells stably transfected with functional OATs. Na+-K+-ATPase was immunolocalized to the BLM along the entire human nephron. NaDC3-related immunostaining was detected in the BLM of proximal tubules and in the BLM and/or luminal membrane of principal cells in connecting segments and collecting ducts. The thin and thick ascending limbs, macula densa, and distal tubules exhibited no reactivity with the anti-NaDC3 antibody. OAT1–OAT3-related immunostaining in human kidneys was detected only in the BLM of cortical proximal tubules; all three OATs were stained more intensely in S1/S2 segments compared with S3 segment in medullary rays, whereas the S3 segment in the outer stripe remained unstained. Expression of NaDC3, OAT1, OAT2, and OAT3 proteins exhibited considerable interindividual variability in both male and female kidneys, and sex differences in their expression could not be detected. Our experiments provide a side-by-side comparison of basolateral transporters cooperating in renal OA secretion in the human kidney.

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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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Moss, Darren M., Wai San Kwan, Neill J. Liptrott, Darren L. Smith, Marco Siccardi, Saye H. Khoo, David J. Back, and Andrew Owen. "Raltegravir Is a Substrate for SLC22A6: a Putative Mechanism for the Interaction between Raltegravir and Tenofovir." Antimicrobial Agents and Chemotherapy 55, no. 2 (November 15, 2010): 879–87. http://dx.doi.org/10.1128/aac.00623-10.

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ABSTRACTThe identification of transporters of the HIV integrase inhibitor raltegravir could be a factor in an understanding of the pharmacokinetic-pharmacodynamic relationship and reported drug interactions of raltegravir. Here we determined whether raltegravir was a substrate for ABCB1 or the influx transporters SLCO1A2, SLCO1B1, SLCO1B3, SLC22A1, SLC22A6, SLC10A1, SLC15A1, and SLC15A2. Raltegravir transport by ABCB1 was studied with CEM, CEMVBL100, and Caco-2 cells. Transport by uptake transporters was assessed by using aXenopus laevisoocyte expression system, peripheral blood mononuclear cells, and primary renal cells. The kinetics of raltegravir transport and competition between raltegravir and tenofovir were also investigated using SLC22A6-expressing oocytes. Raltegravir was confirmed to be an ABCB1 substrate in CEM, CEMVBL100, and Caco-2 cells. Raltegravir was also transported by SLC22A6 and SLC15A1 in oocyte expression systems but not by other transporters studied. TheKmandVmaxfor SLC22A6 transport were 150 μM and 36 pmol/oocyte/h, respectively. Tenofovir and raltegravir competed for SLC22A6 transport in a concentration-dependent manner. Raltegravir inhibited 1 μM tenofovir with a 50% inhibitory concentration (IC50) of 14.0 μM, and tenofovir inhibited 1 μM raltegravir with an IC50of 27.3 μM. Raltegravir concentrations were not altered by transporter inhibitors in peripheral blood mononuclear cells or primary renal cells. Raltegravir is a substrate for SLC22A6 and SLC15A1 in the oocyte expression system. However, transport was limited compared to endogenous controls, and these transporters are unlikely to have a great impact on raltegravir pharmacokinetics.

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Martinez, Alfonso, Antonio Valdivia, Dora Pascual-Salcedo, Alejandro Balsa, Concepcion Nunez, Benjamin Fenandez-Gutierrez, Emilio Gomez de la Concha, and Elena Urcelay. "F.74. Role of SLC22A4, SLC22A5 and RUNX1 Genes in Rheumatoid Arthritis." Clinical Immunology 119 (January 2006): S77. http://dx.doi.org/10.1016/j.clim.2006.04.114.

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Bene, Judit, Katalin Komlósi, Lili Magyari, Gábor Talián, Krisztina Horváth, Beáta Gasztonyi, Pál Miheller, et al. "Plasma carnitine ester profiles in Crohn's disease patients characterized for SLC22A4 C1672T and SLC22A5 G-207C genotypes." British Journal of Nutrition 98, no. 2 (August 2007): 345–50. http://dx.doi.org/10.1017/s0007114507705020.

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Crohn's disease (CD) is a chronic inflammatory bowel disorder caused by environmental and genetic factors. The purpose of this study was to analyse the possible influence of functional variants of genes of OCTN cation transporters on the carnitine ester profile of patients with CD. Genotyping for SLC22A4 1672C → T, SLC22A5-207G → C mutations and three common NOD2 variants (R702W, G908R and 1007finsC) were performed in 100 adult CD patients and in ninety-four healthy controls by direct sequencing. The carnitine ester profile was determined using ESI triple quadrupole tandem MS. Contrary to the NOD2/CARD15 mutations, none of the SLC variants showed increased prevalence in the CD group, the prevalence of TC haplotype did not differ between the patients and the controls. In the mixed group of CD patients the fasting propionyl- (0·243 (sem0·008)v.0·283 (sem0·014) μmol/l), butyryl- (0·274 (sem0·009)v.0·301 (sem0·013)) and isovalerylcarnitine (0·147 (sem0·006)v.0·185 (sem0·009)) levels were decreased; while the level of octenoyl- (0·086 (sem0·006)v.0·069 (sem0·005)), myristoleyl- (0·048 (sem0·003)v.0·037 (sem0·003)), palmitoyl- (0·140 (sem0·005)v.0·122 (sem0·004)) and oleylcarnitine (0·172 (sem0·006)v.0·156 (sem0·008);P < 0·05 in all comparisons) were increased. After sorting the patients into SLC22A genotype-specific subgroups, no significant differences could be observed between them. The carnitine ester profile data suggest selective involvement of the carnitine esters in CD patients, probably due to their altered metabolism.

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Koehler, M. R., B. Wissinger, V. Gorboulev, H. Koepsell, and M. Schmid. "The two human organic cation transporter genes SLC22A1 and SLC22A2 are located on chromosome 6q26." Cytogenetic and Genome Research 79, no. 3-4 (1997): 198–200. http://dx.doi.org/10.1159/000134720.

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Lakner, Lilla, Veronika Csöngei, Lili Magyari, Márta Varga, Pál Miheller, Patrícia Sarlós, Péter Orosz, et al. "Possible role of selected IGR and SLC22A4/SLC22A5 loci in development of inflammatory bowel diseases." Orvosi Hetilap 150, no. 29 (July 1, 2009): 1375–80. http://dx.doi.org/10.1556/oh.2009.28677.

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Az idiopathiás krónikus gyulladásos bélbetegség kialakulásában környezeti tényezők, immunológiai és genetikai faktorok egyaránt szerepet játszanak. Az utóbbi években a CARD15 gén mellett egyre több adat támasztja alá más gének, többek között az 5q31-33 régióban elhelyezkedő IBD5 locus (MIM#606348) szerepét. Egyes tanulmányok ezen régióban az SLC22A4 gén C1672T szubsztitúciójának, illetve az SLC22A5 gén G-207C transzverziójának együttes szerepét hangsúlyozzák, különösen Crohn-betegség kialakulásában, míg más szerzők új minor hajlamosító tényezőket azonosítottak az IBD5 kromoszómarégióban, ezek az IGR-variánsok. Célkitűzés: Az SLC22A4 C1672T és SLC22A5 G-207C mutációk mellett az IGR2096a_1 (rs12521868) és az IGR2198a_1 (rs11739135) polimorfizmusok szerepének vizsgálata gyulladásos bélbetegség kialakulásában. Betegek és módszer: Vizsgálatunk során 440 gyulladásos bélbeteg (206 Crohn- és 234 colitis ulcerosás beteg), valamint 279 kontrollegyén perifériás vérmintájából PCR-RFLP technikával végeztünk DNS-analízist. Eredmények: Sem a C1672T, sem a G-207C allélek, sem a TC haplotípus nem bizonyult rizikófaktornak sem Crohn-betegség, sem colitis ulcerosa esetében. Ezzel ellentétben mindkét minor IGR allél frekvenciája: mind az IGR2096a_1 T (48,1%), mind az IGR2198a_1 C (46,1%) szignifikánsan magasabb volt Crohn-betegségben a kontrollokéhoz (38,5%, 38,4%) képest (p<0,05). Korra és nemre standardizált regressziós analízissel mindkét allélnél fokozott rizikót észleltünk Crohn-betegség vonatkozásában (T-allél: OR=1,694, 95%-os CI: 1,137–2,522, p=0,010, C-allél: OR=1,644, 95%-os CI=1,103–2,449, p=0,015). Colitis ulcerosa esetén nem találtunk összefüggést a két IGR-variáns és a betegség kialakulása között. Következtetés: az IGR minor alléleknek a környező kaukázusi népcsoportoktól eltérően magyarországi populációban szerepük lehet a Crohn-betegség kialakulásában.

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Antonescu, Irina E., Maria Karlgren, Maria L. Pedersen, Ivailo Simoff, Christel A. S. Bergström, Sibylle Neuhoff, Per Artursson, Bente Steffansen, and Carsten Uhd Nielsen. "Acamprosate Is a Substrate of the Human Organic Anion Transporter (OAT) 1 without OAT3 Inhibitory Properties: Implications for Renal Acamprosate Secretion and Drug–Drug Interactions." Pharmaceutics 12, no. 4 (April 24, 2020): 390. http://dx.doi.org/10.3390/pharmaceutics12040390.

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Acamprosate is an anionic drug substance widely used in treating symptoms of alcohol withdrawal. It was recently shown that oral acamprosate absorption is likely due to paracellular transport. In contrast, little is known about the eliminating mechanism clearing acamprosate from the blood in the kidneys, despite the fact that studies have shown renal secretion of acamprosate. The hypothesis of the present study was therefore that renal organic anion transporters (OATs) facilitate the renal excretion of acamprosate in humans. The aim of the present study was to establish and apply OAT1 (gene product of SLC22A6) and OAT3 (gene product of SLC22A8) expressing cell lines to investigate whether acamprosate is a substrate or inhibitor of OAT1 and/or OAT3. The studies were performed in HEK293-Flp-In cells stably transfected with SLC22A6 or SLC22A8. Protein and functional data showed that the established cell lines are useful for studying OAT1- and OAT3-mediated transport in bi-laboratory studies. Acamprosate inhibited OAT1-mediated p-aminohippuric acid (PAH) uptake but did not inhibit substrate uptake via OAT3 expressing cells, neither when applied concomitantly nor after a 3 h preincubation with acamprosate. The uptake of PAH via OAT1 was inhibited in a competitive manner by acamprosate and cellular uptake studies showed that acamprosate is a substrate for OAT1 with a Km-value of approximately 700 µM. Probenecid inhibited OAT1-mediated acamprosate uptake with a Ki-value of approximately 13 µM, which may translate into an estimated clinically significant DDI index. In conclusion, acamprosate was identified as a substrate of OAT1 but not OAT3.

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Breljak, Davorka, Hrvoje Brzica, Douglas H. Sweet, Naohiko Anzai, and Ivan Sabolic. "Sex-dependent expression of Oat3 (Slc22a8) and Oat1 (Slc22a6) proteins in murine kidneys." American Journal of Physiology-Renal Physiology 304, no. 8 (April 15, 2013): F1114—F1126. http://dx.doi.org/10.1152/ajprenal.00201.2012.

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In the mouse kidney, organic anion transporter 3 (mOat3, Slc22a8) was previously localized to the basolateral membrane (BLM) of proximal tubule (PT), thick ascending limb of Henle, macula densa, distal tubule, and cortical collecting duct. However, the specificity of anti-Oat3 antibodies (Oat3-Ab) used in these studies was not properly verified. Moreover, the sex-dependent expression of mOat3, and of the functionally similar transporter mOat1 (Slc22a6), in the mouse kidney has been studied at mRNA level, whereas their protein expression is poorly documented. Here we investigated 1) specificity of Oat3-Abs by using Oat3 knockout (KO) mice, 2) cell localization of renal mOat3 with a specific mOat3-Ab, 3) sex-dependent expression of renal mOat3 and mOat1 proteins, and 4) hormone(s) responsible for observed sex differences. As previously shown, an Oat3-Ab against the rat protein stained the BLM of various nephron segments in wild-type (WT) mice, but the same staining pattern was noted along the nephron of Oat3 KO mice. However, the mOat3-Ab exclusively stained the BLM of PT in WT mice, where it colocalized with the mOat1 protein, whereas no staining of Oat3 protein was noted in the kidney of Oat3 KO mice. The expression of mOat3 protein was lower in male mice, upregulated by castration, and downregulated by testosterone treatment. The expression of mOat1 protein was stronger in males, downregulated by castration, and upregulated by testosterone treatment. Thus, at the protein level, mOat3 and mOat1 exhibit sex-dependent expression with an opposite pattern; mOat3 is female dominant due to androgen inhibition, while mOat1 is male dominant due to androgen stimulation.

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FENG, Yun, Ping ZHENG, Hang ZHAO, and Kai WU. "SLC22A4 and SLC22A5 gene polymorphisms and Crohn's disease in the Chinese Han population." Journal of Digestive Diseases 10, no. 3 (August 2009): 181–87. http://dx.doi.org/10.1111/j.1751-2980.2009.00383.x.

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Butt, C., S. Sun, C. Greenwood, D. Gladman, and P. Rahman. "Lack of association of SLC22A4, SLC22A5, SLC9A3R1 and RUNX1 variants in psoriatic arthritis." Rheumatology 44, no. 6 (March 15, 2005): 820–21. http://dx.doi.org/10.1093/rheumatology/keh606.

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Barros, Scott A., Chutima Srimaroeng, Jennifer L. Perry, Ramsey Walden, Neetu Dembla-Rajpal, Douglas H. Sweet, and John B. Pritchard. "Activation of Protein Kinase Cζ Increases OAT1 (SLC22A6)- and OAT3 (SLC22A8)-mediated Transport." Journal of Biological Chemistry 284, no. 5 (November 21, 2008): 2672–79. http://dx.doi.org/10.1074/jbc.m808078200.

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Yamazaki, Keiko, Masakazu Takazoe, Torao Tanaka, Toshiki Ichimori, Susumu Saito, Aritoshi Iida, Yoshihiro Onouchi, Akira Hata, and Yusuke Nakamura. "Association analysis of SLC22A4, SLC22A5 and DLG5 in Japanese patients with Crohn disease." Journal of Human Genetics 49, no. 12 (October 19, 2004): 664–68. http://dx.doi.org/10.1007/s10038-004-0204-x.

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Bhatnagar, Vibha, Gang Xu, Bruce A. Hamilton, David M. Truong, Satish A. Eraly, Wei Wu, and Sanjay K. Nigam. "Analyses of 5′ regulatory region polymorphisms in human SLC22A6 (OAT1) and SLC22A8 (OAT3)." Journal of Human Genetics 51, no. 6 (April 29, 2006): 575–80. http://dx.doi.org/10.1007/s10038-006-0398-1.

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Sánchez Rodríguez, Luz Helena, Olga Marcela Medina Pérez, Fernando Rondón González, Giovanna Rincón Cruz, Linda Rocha Muñoz, and Oscar Flórez-Vargas. "Genetic Polymorphisms in Multispecific Transporters Mitigate Mercury Nephrotoxicity in an Artisanal and Small-Scale Gold Mining Community in Colombia." Toxicological Sciences 178, no. 2 (September 18, 2020): 338–46. http://dx.doi.org/10.1093/toxsci/kfaa142.

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Abstract In artisanal and small-scale gold mining, occupational exposure to mercury (Hg) vapor is related to harmful effects on several organs, including the kidneys. We previously reported significantly increased levels of Hg in blood and urine despite normal kidney function in individuals from Colombia occupationally exposed to Hg compared with those nonexposed. We evaluated the contribution of 4 genetic variants in key genes encoding the transporters solute carrier (SLC; rs4149170 and rs4149182) and ATP-binding cassette(ABC; rs1202169 and rs1885301) in the pathogenesis of nephrotoxicity due to Hg exposure in these groups. Regression analysis was performed to determine the association between the blood- and urine-Hg concentration with SLC and ABC polymorphisms in 281 Colombian individuals (160 exposed and 121 nonexposed to Hg). We found an enrichment of ABCB1 rs1202169-T allele in the exposed group (p = .011; OR= 2.05; 95% CI = 1.18–3.58) compared with the nonexposure group. We also found that carriers of SLC22A8 rs4149182-G and ABCB1 rs1202169-T alleles had a higher urinary clearance rate of Hg than noncarriers (β = 0.13, p = .04), whereas carriers of SLC22A6 rs4149170-A and ABCB1 rs1202169-C alleles showed abnormal levels of estimated glomerular filtration rate (β = −84.96, p = .040) and beta-2-microglobulin (β = 743.38, p < .001). Our results suggest that ABCB1 rs1202169 and its interaction with SLC22A8 rs4149182 and SLC22A6 rs4149170 could mitigate Hg nephrotoxicity by controlling the renal proximal tubule cell accumulation of inorganic Hg. This will be useful to estimate the risk of kidney toxicity associated to Hg and the genetic selection to aid adaptation to Hg-rich environments.

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Chaves, Catarina, Federica Campanelli, Hélène Chapy, David Gomez-Zepeda, Fabienne Glacial, Maria Smirnova, Meryam Taghi, et al. "An Interspecies Molecular and Functional Study of Organic Cation Transporters at the Blood-Brain Barrier: From Rodents to Humans." Pharmaceutics 12, no. 4 (March 28, 2020): 308. http://dx.doi.org/10.3390/pharmaceutics12040308.

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Organic cation transporters (OCTs) participate in the handling of compounds in kidneys and at the synaptic cleft. Their role at the blood-brain barrier (BBB) in brain drug delivery is still unclear. The presence of OCT1,2,3 (SLC22A1-3) in mouse, rat and human isolated brain microvessels was investigated by either qRT-PCR, quantitative proteomics and/or functional studies. BBB transport of the prototypical substrate [3H]-1-methyl-4-phenylpyridinium ([3H]-MPP+) was measured by in situ brain perfusion in six mouse strains and in Sprague Dawley rats, in primary human brain microvascular endothelial cells seeded on inserts, in the presence or absence of OCTs and a MATE1 (SLC49A1) inhibitor. The results show negligible OCT1 (SLC22A1) and OCT2 (SLC22A2) expression in either mice, rat or human brain microvessels, while OCT3 expression was identified in rat microvessels by qRT-PCR. The in vitro human cellular uptake of [3H]-MPP+ was not modified by OCTs/MATE-inhibitor. Brain transport of [3H]-MPP+ remains unchanged between 2- and 6-month old mice, and no alteration was observed in mice and rats with inhibitors. In conclusion, the evidenced lack of expression and/or functional OCTs and MATE at the BBB allows the maintenance of the brain homeostasis and function as it prevents an easy access of their neurotoxicant substrates to the brain parenchyma.

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Díaz, N. Paniagua, E. Tranquilino Batres, L. Sánchez Chapul, A. P. López Flores, A. L. Álvarez Grijalva, A. Lózano Cardenas, F. Sánchez Muñoz, and A. López Macay. "Study of Epigenetic Control of TLR2, TLR4, SLC2A9, SLC22A12, SLC22A3 and ABCG2 Genes in Leukocytes of Gout Patients." Osteoarthritis and Cartilage 25 (April 2017): S215. http://dx.doi.org/10.1016/j.joca.2017.02.372.

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Bene, Judit. "Prevalence of SLC22A4, SLC22A5 and CARD15 gene mutations in Hungarian pediatric patients with Crohn’s disease." World Journal of Gastroenterology 12, no. 34 (2006): 5550. http://dx.doi.org/10.3748/wjg.v12.i34.5550.

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Knapstein, J., M. Heise, A. Lautem, J. Schattenberg, P. R. Galle, G. Otto, M. Schuchmann, and T. Zimmermann. "285 DOWNREGULATION OF ORGANIC CATION TRANSPORTERS OCT1 (SLC22A1) AND OCT3 (SLC22A3) IN HUMAN HEPATOCELLULAR CARCINOMA AND THEIR PROGNOSTIC SIGNIFICANCE." Journal of Hepatology 56 (April 2012): S118. http://dx.doi.org/10.1016/s0168-8278(12)60298-0.

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Magyari, Lili, Judit Bene, Katalin Komlósi, Gábor Talián, Bernadett Faragó, Veronika Csöngei, Luca Járomi, et al. "Prevalence of SLC22A4 1672T and SLC22A5 −207C combination defined TC haplotype in Hungarian ulcerative colitis patients." Pathology & Oncology Research 13, no. 1 (March 2007): 53–56. http://dx.doi.org/10.1007/bf02893441.

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Nies, Anne T., Hermann Koepsell, Stefan Winter, Oliver Burk, Kathrin Klein, Reinhold Kerb, Ulrich M. Zanger, Dietrich Keppler, Matthias Schwab, and Elke Schaeffeler. "Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver." Hepatology 50, no. 4 (May 28, 2009): 1227–40. http://dx.doi.org/10.1002/hep.23103.

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Fu, Li, Yan-Ru Qin, Xiao-Yan Ming, Xian-Bo Zuo, Yu-Wen Diao, Li-Yi Zhang, Jiaoyu Ai, et al. "RNA editing of SLC22A3 drives early tumor invasion and metastasis in familial esophageal cancer." Proceedings of the National Academy of Sciences 114, no. 23 (May 22, 2017): E4631—E4640. http://dx.doi.org/10.1073/pnas.1703178114.

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Like many complex human diseases, esophageal squamous cell carcinoma (ESCC) is known to cluster in families. Familial ESCC cases often show early onset and worse prognosis than the sporadic cases. However, the molecular genetic basis underlying the development of familial ESCC is mostly unknown. We reported that SLC22A3 is significantly down-regulated in nontumor esophageal tissues from patients with familial ESCC compared with tissues from patients with sporadic ESCCs. A-to-I RNA editing of the SLC22A3 gene results in its reduced expression in the nontumor esophageal tissues of familial ESCCs and is significantly correlated with lymph node metastasis. The RNA-editing enzyme ADAR2, a familial ESCC susceptibility gene identified by our post hoc genome-wide association study, is positively correlated with the editing level of SLC22A3. Moreover, functional studies showed that SLC22A3 is a metastasis suppressor in ESCC, and deregulation of SLC22A3 facilitates cell invasion and filopodia formation by reducing its direct association with α-actinin-4 (ACTN4), leading to the increased actin-binding activity of ACTN4 in normal esophageal cells. Collectively, we now show that A-to-I RNA editing of SLC22A3 contributes to the early development and progression of familial esophageal cancer in high-risk individuals.

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Pozdnyakov, N. O., I. N. Kagarmanyan, A. E. Miroshnikov, E. S. Emelyanov, A. A. Gruzdeva, A. M. Sirotkina, I. A. Dukhanina, A. A. Milkina, A. A. Khokhlov, and S. O. Pozdnyakov. "Pharmacogenetic Aspects of Type 2 Diabetes Treatment." Acta Biomedica Scientifica 5, no. 3 (July 13, 2020): 13–23. http://dx.doi.org/10.29413/abs.2020-5.3.2.

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In this article, we analyze the role of different variants of the KCNJ11, TCF7L2, SLC22A1, SLC22A3, CYP2C9, CYP2C8, PPARγ genes polymorphisms in efficacy of diabetes mellitus pharmacotherapy. T allele of the KCNJ11 rs2285676 gene polymorphism and G allele of KCNJ11 rs5218 gene polymorphism are associated with the response to IDPP-4 therapy; the presence of KCNJ11 gene rs5210 polymorphism A allele is a predictor of poor response. The effect of rs7903146 polymorphism of TCF7L2 gene was evaluated on the response to treatment of patients taking linagliptin. Linagliptin significantly reduced HbA1c levels for all three rs7903146 genotypes (CC: –0.82 %; CT: –0.77 %; TT: –0.57 %). A significantly smaller effect of therapy was observed with the genotype with ТТ. The rs622342 polymorphism of SLC22A1 gene was studied in effectiveness of metformin. The researches demonstrated that carriers of variant AA had an average decrease of HbA1c of 0.53 %, heterozygous – decrease of 0.32 %, and carriers of a minor variant of SS had an increase of 0.2 % in the level of HbA1c. A significant effect of CYP2C9 polymorphisms on the pharmacokinetic parameters of PSM was noted. When studying the kinetics of glibenclamide, it was found that carriage of the allele *2 significantly reduces glibenclamide metabolism: homozygous carriers had clearance 90 % lower than homozygous carriers of the wild variant. The studies confirmed the association of the allelic variants of Thr394Thr and Gly482Ser of PPARγ gene with higher efficacy of the rosiglitazone. The data obtained from the analysis of the association of the Pro12Ala polymorphism of PPARγ gene and the response to therapy is contradictory. Thus the personalized approach, based on the knowledge of polymorphism options, will allow choosing the most effective drug with transparent kinetics for each individual patient.

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Journal articles on the topic 'SLC22A23'

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