Inflammation and Organic Cation Transporters Novel (OCTNs).

Inflammation is a physiological condition characterized by a complex interplay between different cells handled by metabolites and specific inflammatory-related molecules. In some pathological situations, inflammation persists underlying and worsening the pathological state. Over the years, two membrane transporters namely OCTN1 (SLC22A4) and OCTN2 (SLC22A5) have been shown to play specific roles in inflammation. These transporters form the OCTN subfamily within the larger SLC22 family. The link between these proteins and inflammation has been proposed based on their link to some chronic inflammatory diseases such as asthma, Crohn's disease (CD), and rheumatoid arthritis (RA). Moreover, the two transporters show the ability to mediate the transport of several compounds including carnitine, carnitine derivatives, acetylcholine, ergothioneine, and gut microbiota by-products, which have been specifically associated with inflammation for their anti- or proinflammatory action. Therefore, the absorption and distribution of these molecules rely on the presence of OCTN1 and OCTN2, whose expression is modulated by inflammatory cytokines and transcription factors typically activated by inflammation. In the present review, we wish to provide a state of the art on OCTN1 and OCTN2 transport function and regulation in relationships with inflammation and inflammatory diseases focusing on the metabolic signature collected in different body districts and gene polymorphisms related to inflammatory diseases.

Overexpression of Slc22a18 facilitates fat accumulation in mice.

We previously reported that solute carrier family 22 member 18 (Slc22a18) regulates lipid accumulation in 3T3-L1 adipocytes. Here, we provide additional evidence derived from experiments with adenoviral vector expression and genetic manipulation of mice. In primary cultured rat hepatocytes, adenoviral overexpression of mouse Slc22a18 increased triglyceride accumulation and triglyceride synthetic activity, which was decreased in an adenoviral knockdown experiment. Adenoviral overexpression of mouse Slc22a18 in vivo caused massive fatty liver in mice, even under normal dietary conditions. Conversely, adenoviral knockdown of mouse Slc22a18 reduced hepatic lipid accumulation induced by a high-glucose and high-sucrose diet. We created Slc22a18 knockout mice, which grew normally and showed no obvious spontaneous phenotypes. However, compared with control littermates, the knockout mice exhibited decreased hepatic triglyceride content under refeeding conditions, significantly reduced epididymal fat mass, and tended to have lower liver weight in conjunction with leptin deficiency. Finally, we created transgenic mice overexpressing rat Slc22a18 in an adipose-specific manner, which had increased body weight and epididymal fat mass primarily because of increased adipocyte cell volume. In these transgenic mice, a positive correlation was observed between adiposity and the expression levels of the rat Slc22a18 transgene. Taken together, these results indicate that Slc22a18 has positive effects on lipid accumulation in vivo.

Metformin inhibits OCTN1- and OCTN2-mediated hepatic accumulation of doxorubicin and alleviates its hepatotoxicity in mice.

Doxorubicin (DOX) is a widely used antitumor agent; however, its clinical application is limited by dose-related organ damage. Because organic cation/carnitine transporters (OCTN1 and OCTN2), which are critical for DOX uptake, are highly expressed in hepatocytes, we aimed to elucidate the role of these transporters in hepatic DOX uptake. The results indicated that inhibitors and RNA interference both significantly reduced DOX accumulation in HepG2 and HepaRG cells, suggesting that OCTN1/2 contribute substantially to DOX uptake by hepatocytes. To determine whether metformin (MET, an inhibitor of OCTN1 and OCTN2) ameliorates DOX-induced hepatotoxicity, we conducted in vitro and in vivo studies. MET (1-100 µM) inhibited DOX (500 nM) accumulation and cytotoxicity in vitro in a concentration-dependent manner. Furthermore, intravenous MET administration at 250 or 500 mg/kg or by gavage at 50, 100, or 200 mg/kg reduced DOX (8 mg/kg) accumulation in a dose-dependent manner in the mouse liver and attenuated the release of alanine aminotransferase, aspartate aminotransferase, and carboxylesterase 1. Additionally, MET reduced the distribution of DOX in the heart, liver, and kidney and enhanced the urinary elimination of DOX; however, it did not increase the nephric toxicity of DOX. In conclusion, our study demonstrated that MET alleviates DOX hepatotoxicity by inhibiting OCTN1- and OCTN2-mediated DOX uptake in vitro (mouse hepatocytes and HepaRG or HepG2 cells) and in mice.

The effect of genetic variants of SLC22A18 on proliferation, migration, and invasion of colon cancer cells.

Solute carrier family (SLC) transporters are expressed in the digestive system and play important roles in maintaining physiological functions in the body. In addition, SLC transporters act as oncoproteins or tumor-suppressor proteins during the development, progression, and metastasis of various digestive system cancers. SLC22A18, a member of the SLC22 gene family, is an orphan transporter with an unknown endogenous substrate. Previous study revealed that SLC22A18 is downregulated in colorectal cancer tissues and that it acts as a suppressor in colorectal cancer, although the effects of SLC22A18 variants on colon cancer cell proliferation, migration, and invasion are unknown. Therefore, in this study, we identified SLC22A18 variants found in multiple populations by searching public databases and determined the in vitro effects of these missense variations on transporter expression and cancer progression. Our results indicated that three missense SLC22A18 variants-p.Ala6Thr, p.Arg12Gln, and p.Arg86His-had significantly lower cell expression than the wild type, possibly owing to intracellular degradation. Furthermore, these three variants caused significantly higher proliferation, migration, and invasion of colon cancer cells than the wild type. Our findings suggest that missense variants of SLC22A18 can potentially serve as biomarkers or prognostic tools that enable clinicians to predict colorectal cancer progression.

Identification and characterization of an endogenous biomarker of the renal vectorial transport (OCT2-MATE1).

The renal tubular organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1) mediate the vectorial elimination of many drugs and toxins from the kidney, and endogenous biomarkers for vectorial transport (OCT2-MATE1) would allow more accurate drug dosing and help to characterize drug-drug interactions and toxicity. Human serum uptake in OCT2-overexpressing cells and metabolomics analysis were carried out. Potential biomarkers were verified in vitro and in vivo. The specificity of biomarkers was validated in renal transporter overexpressing cells and the sensitivity was investigated by Km . The results showed that the uptake of thiamine, histamine, and 5-hydroxytryptamine was significantly increased in OCT2-overexpressing cells. In vitro assays confirmed that thiamine, histamine, and 5-hydroxytryptamine were substrates of both OCT2 and MATE1. In vivo measurements indicated that the serum thiamine level was increased significantly in the presence of the rOCT2 inhibitor cimetidine, and the level in renal tissue was increased significantly by the rMATE1 inhibitor pyrimethamine. There were no significant changes in the uptake or efflux of thiamine in cell lines overexpressed OAT1, OAT2, OAT3, MRP4, organic anion transporting polypeptide 4C1, P-gp, peptide transporter 2, urate transporter 1, and OAT4. The Km for thiamine with OCT2 and MATE1 were 71.2 and 10.8 µM, respectively. In addition, the cumulative excretion of thiamine at 2 and 4 h was strongly correlated with metformin excretion (R2  > 0.6). Thus, thiamine is preferentially secreted by the OCT2 and MATE1 in renal tubules and can provide a reference value for evaluating the function of the renal tubular OCT2-MATE1.

Genotype and Phenotype of Renal Hypouricemia: A Single-Center Study from China.

BACKGROUND: Renal hypouricemia (RHUC), a rare inherited disorder characterized by impaired uric acid reabsorption and subsequent profound hypouricemia, occurs mainly due to variants in SLC22A12 or SLC2A9. Only anecdotal cases and one small-scale RHUC screening study have been reported in the Chinese population. METHODS: A total of 19 patients with RHUC from 17 unrelated families were recruited from our center. The medical history, clinical manifestations, biochemical exam, and clinical outcomes were collected. Next-generation sequencing-based targeted gene sequencing or whole exon sequencing was performed. RESULTS: A total of 22 variants in SLC22A12 or SLC2A9 were found in 19 patients. The variant c.944G>A (p.W315X) in SLC2A9 was identified in three patients. Three variants c.165C>A (p.D55E), c.1549_1555delGAGACCC (p.E517Rfs*17), and c.1483T>C (p.W495R) in SLC22A12 and three variants c.1215+1G>A (splicing variant), c.643A>C (p.T215P), and c.227C>A (p.S76X) in SLC2A9 were novel. A proportion of 10 out of 19 patients presented with exercise-induced acute kidney injury (EIAKI). The renal outcome was favorable. Five patients had nephrolithiasis, in whom three had hypercalciuria. CONCLUSION: The current study reported six novel variants in SLC22A12 and SLC2A9 genes of Chinese patients with RHUC. The variant c.944G>A (p.W315X) in SLC2A9 may be common in Chinese patients. EIAKI is the main clinical phenotype associated with RHUC in our cohort, with a favorable outcome. Hypercalciuria presented in some RHUC patients is a new finding.

Recurrent exercise-induced acute kidney injury associated with hypouricemia: a case report and literature review.

BACKGROUND: Hereditary renal hypouricemia (RHUC) is a heterogenous disorder characterized by defective uric acid (UA) reabsorption resulting in hypouricemia and increased fractional excretion of UA. RHUC is an important cause of exercise-induced acute kidney injury (EIAKI), nephrolithiasis and posterior reversible encephalopathy syndrome (PRES). We present here an unusual case of a patient with RHUC who presented with recurrent EIAKI and had two heterozygous mutations in the SLC2A9 gene. CASE PRESENTATION: A 43-year old man was admitted to our clinic because of bilateral loin pain, nausea and sleeplessness for 3 days after strenuous exercise. The laboratory results revealed increased levels of blood urea nitrogen (BUN) (15 mmol/l) and serum creatinine (Scr) (450 µmol/l), while the UA level was extremely low at 0.54 mg/dl, and his fractional excretion of urate (FE-UA) was 108%. The patient had an episode of acute kidney injury after playing soccer approximately 20 years ago, and on routine physical examination, his UA was less than 0.50 mg/dl. In view of the marked hypouricemia and high FE-UA, a diagnosis of RHUC was suspected, which led us to perform mutational screening of the SLC22A12 and SLC2A9 genes. DNA sequencing revealed no mutation in SLC22A12 gene, but two heterozygous mutations in the SLC2A9 gene. CONCLUSIONS: This is a rare report of a patient with RHUC2 due to the mutation of SLC2A9. And this unique symptom of EIAKI and decreased or normal serum concentrations of UA warrant more attention as an early cue of RHUC.

New SLC22A12 (URAT1) Variant Associated with Renal Hypouricemia Identified by Whole-Exome Sequencing Analysis and Bioinformatics Predictions.

Renal hypouricemia (RHUC) is a rare hereditary disorder caused by loss-of-function mutations in the SLC22A12 (RHUC type 1) or SLC2A9 (RHUC type 2) genes, encoding urate transporters URAT1 and GLUT9, respectively, that reabsorb urate in the renal proximal tubule. The characteristics of this disorder are low serum urate levels, high renal fractional excretion of urate, and occasional severe complications such as nephrolithiasis and exercise-induced acute renal failure. In this study, we report two Spanish (Caucasian) siblings and a Pakistani boy with clinical characteristics compatible with RHUC. Whole-exome sequencing (WES) analysis identified two homozygous variants: a novel pathogenic SLC22A12 variant, c.1523G>A; p.(S508N), in the two Caucasian siblings and a previously reported SLC2A9 variant, c.646G>A; p.(G216R), in the Pakistani boy. Our findings suggest that these two mutations cause RHUC through loss of urate reabsorption and extend the SLC22A12 mutation spectrum. In addition, this work further emphasizes the importance of WES analysis in clinical settings.

Role of Mouse Organic Cation Transporter 2 for Nephro- and Peripheral Neurotoxicity Induced by Chemotherapeutic Treatment with Cisplatin.

Cisplatin (CDDP) is an efficient chemotherapeutic agent broadly used to treat solid cancers. Chemotherapy with CDDP can cause significant unwanted side effects such as renal toxicity and peripheral neurotoxicity. CDDP is a substrate of organic cation transporters (OCT), transporters that are highly expressed in renal tissue. Therefore, CDDP uptake by OCT may play a role in causing unwanted toxicities of CDDP anticancer treatment. In this study, the contribution of the mouse OCT2 (mOCT2) to CDDP nephro- and peripheral neurotoxicity was investigated by comparing the effects of cyclic treatment with low doses of CDDP on renal and neurological functions in wild-type (WT) mice and mice with genetic deletion of OCT2 (OCT2-/- mice). This CDDP treatment protocol caused significant impairment of kidneys and peripherical neurological functions in WT mice. These effects were significantly reduced in OCT2-/- mice, however, less profoundly than what was previously measured in mice with genetic deletion of both OCT1 and 2 (OCT1-2-/- mice). Comparing the apparent affinities (IC50) of mOCT1 and mOCT2 for CDDP, the mOCT1 displayed a higher affinity for CDDP than the mOCT2 (IC50: 9 and 558 µM, respectively). Also, cellular toxicity induced by incubation with 100 µM CDDP was more pronounced in cells stably expressing mOCT1 than in cells expressing mOCT2. Therefore, in mice, CDDP uptake by both OCT1 and 2 contributes to the development of CDDP undesired side effects. OCT seem to be suitable targets for establishing treatment protocols aimed at decreasing unwanted CDDP toxicity and improving anticancer treatment with CDDP.

GLUT9 as a potential drug target for chronic kidney disease: Drug target validation by a Mendelian randomization study.

Although chronic kidney disease (CKD) is recognized as a major public health concern, effective treatment strategies have yet to be developed. Identification and validation of drug targets are key issues in the development of therapeutic agents for CKD. Uric acid (UA), a major risk factor for gout, has also been suggested to be a risk factor for CKD, but the efficacy of existing urate-lowering therapies for CKD is controversial. We focused on five uric acid transporters (ABCG2, SLC17A1, SLC22A11, SLC22A12, SLC2A9) as potential drug targets and evaluated the causal association between serum UA levels and estimated glomerular filtration rate (eGFR) using single-SNP Mendelian Randomization. The results showed a causal association between genetically predicted changes in serum UA levels and eGFR when genetic variants were selected from the SLC2A9 locus. Estimation based on a loss-of-function mutation (rs16890979) showed that the changes in eGFR per unit increase in serum UA level was -0.0082 ml/min/1.73 m2 (95% CI -0.014 to -0.0025, P = 0.0051). These results indicate that SLC2A9 may be a novel drug target for CKD that preserves renal function through its urate-lowering effect.

Population pharmacokinetics, pharmacodynamics and pharmacogenetics modelling of oxypurinol in Hmong adults with gout and/or hyperuricemia.

AIMS: The aim of this study was to quantify identifiable sources of variability, including key pharmacogenetic variants in oxypurinol pharmacokinetics and their pharmacodynamic effect on serum urate (SU). METHODS: Hmong participants (n = 34) received 100 mg allopurinol twice daily for 7 days followed by 150 mg allopurinol twice daily for 7 days. A sequential population pharmacokinetic pharmacodynamics (PKPD) analysis with non-linear mixed effects modelling was performed. Allopurinol maintenance dose to achieve target SU was simulated based on the final PKPD model. RESULTS: A one-compartment model with first-order absorption and elimination best described the oxypurinol concentration-time data. Inhibition of SU by oxypurinol was described with a direct inhibitory Emax model using steady-state oxypurinol concentrations. Fat-free body mass, estimated creatinine clearance and SLC22A12 rs505802 genotype (0.32 per T allele, 95% CI 0.13, 0.55) were found to predict differences in oxypurinol clearance. Oxypurinol concentration required to inhibit 50% of xanthine dehydrogenase activity was affected by PDZK1 rs12129861 genotype (-0.27 per A allele, 95% CI -0.38, -0.13). Most individuals with both PDZK1 rs12129861 AA and SLC22A12 rs505802 CC genotypes achieve target SU (with at least 75% success rate) with allopurinol below the maximum dose, regardless of renal function and body mass. In contrast, individuals with both PDZK1 rs12129861 GG and SLC22A12 rs505802 TT genotypes would require more than the maximum dose, thus requiring selection of alternative medications. CONCLUSIONS: The proposed allopurinol dosing guide uses individuals' fat-free mass, renal function and SLC22A12 rs505802 and PDZK1 rs12129861 genotypes to achieve target SU.

In vitro validation of an in vivo phenotyping drug cocktail for major drug transporters in humans.

PURPOSE: Cocktails of transporter probe drugs are used in vivo to assess transporter activity and respective drug-drug interactions. An inhibitory effect of components on transporter activities should be ruled out. Here, for a clinically tested cocktail consisting of adefovir, digoxin, metformin, sitagliptin, and pitavastatin, inhibition of major transporters by individual probe substrates was investigated in vitro. METHODS: Transporter transfected HEK293 cells were used in all evaluations. Cell-based assays were applied for uptake by human organic cation transporters 1/2 (hOCT1/2), organic anion transporters 1/3 (hOAT1/3), multidrug and toxin extrusion proteins 1/2K (hMATE1/2K), and organic anion transporter polypeptide 1B1/3 (hOATP1B1/3). For P-glycoprotein (hMDR1) a cell-based efflux assay was used whereas an inside-out vesicle-based assay was used for the bile salt export pump (hBSEP). All assays used standard substrates and established inhibitors (as positive controls). Inhibition experiments using clinically achievable concentrations of potential perpetrators at the relevant transporter expression site were carried out initially. If there was a significant effect, the inhibition potency (Ki) was studied in detail. RESULTS: In the inhibition tests, only sitagliptin had an effect and reduced hOCT1- and hOCT2- mediated metformin uptake and hMATE2K mediated MPP+ uptake by more than 70%, 80%, and 30%, respectively. The ratios of unbound Cmax (observed clinically) to Ki of sitagliptin were low with 0.009, 0.03, and 0.001 for hOCT1, hOCT2, and hMATE2K, respectively. CONCLUSION: The inhibition of hOCT2 in vitro by sitagliptin is in agreement with the borderline inhibition of renal metformin elimination observed clinically, supporting a dose reduction of sitagliptin in the cocktail.

Pathogenic Variants of SLC22A12 (URAT1) and SLC2A9 (GLUT9) in Spanish Patients with Renal Hypouricemia: Founder Effect of SLC2A9 Variant c.374C>T; p.(T125M).

Renal hypouricemia (RHUC) is a rare inherited disorder characterized by impaired urate reabsorption in the proximal tubule resulting in low urate serum levels and increased urate excretion. Some patients may present severe complications such as exercise-induced acute renal failure and nephrolithiasis. RHUC is caused by inactivating mutations in the SLC22A12 (RHUC type 1) or SLC2A9 (RHUC type 2) genes, which encode urate transporters URAT1 and GLUT9, respectively. In this study, our goal was to identify mutations associated with twenty-one new cases with RHUC through direct sequencing of SLC22A12 and SLC2A9 coding exons. Additionally, we carried out an SNPs-haplotype analysis to determine whether the rare SLC2A9 variant c.374C>T; p.(T125M), which is recurrent in Spanish families with RHUC type 2, had a common-linked haplotype. Six intragenic informative SNPs were analyzed using PCR amplification from genomic DNA and direct sequencing. Our results showed that ten patients carried the SLC22A12 mutation c.1400C>T; p.(T467M), ten presented the SLC2A9 mutation c.374C>T, and one carried a new SLC2A9 heterozygous mutation, c.593G>A; p.(R198H). Patients carrying the SLC2A9 mutation c.374C>T share a common-linked haplotype, confirming that it emerged due to a founder effect.

The Role of Organic Cation Transporters in the Pharmacokinetics, Pharmacodynamics and Drug-Drug Interactions of Tyrosine Kinase Inhibitors.

Tyrosine kinase inhibitors (TKIs) decisively contributed in revolutionizing the therapeutic approach to cancer, offering non-invasive, tolerable therapies for a better quality of life. Nonetheless, degree and duration of the response to TKI therapy vary depending on cancer molecular features, the ability of developing resistance to the drug, on pharmacokinetic alterations caused by germline variants and unwanted drug-drug interactions at the level of membrane transporters and metabolizing enzymes. A great deal of approved TKIs are inhibitors of the organic cation transporters (OCTs). A handful are also substrates of them. These transporters are polyspecific and highly expressed in normal epithelia, particularly the intestine, liver and kidney, and are, hence, arguably relevant sites of TKI interactions with other OCT substrates. Moreover, OCTs are often repressed in cancer cells and might contribute to the resistance of cancer cells to TKIs. This article reviews the OCT interactions with approved and in-development TKIs reported in vitro and in vivo and critically discusses the potential clinical ramifications thereof.

Possible Use of Non-purine Selective Xanthine Oxidoreductase Inhibitors for Prevention of Exercise-induced Acute Kidney Injury Associated with Renal Hypouricemia.

Exercise-induced acute kidney injury (EIAKI) is frequently complicated with renal hypouricemia (RHUC). In patients with RHUC, limiting anaerobic exercise can prevent EIAKI. However, it is challenging to reduce exercise intensity in athletes. We herein report a 16-year-old Japanese football player with familial RHUC with compound heterozygous mutations in urate transporter 1 (URAT1) who presented with recurrent EIAKI. As prophylaxis (hydration during exercise) could not prevent EIAKI, febuxostat was initiated. EIAKI was not observed for 16 months despite exercising intensively. Hence, non-purine-selective xanthine oxidoreductase inhibitors may decrease the incidence of EIAKI in athletes with RHUC.

Polymorphic renal transporters and cisplatin's toxicity in urinary bladder cancer patients: current perspectives and future directions.

Urinary bladder cancer (UBC) holds a potentially profound social burden and affects over 573,278 new cases annually. The disease's primary risk factors include occupational tobacco smoke exposure and inherited genetic susceptibility. Over the past 30 years, a number of treatment modalities have emerged, including cisplatin, a platinum molecule that has demonstrated effectiveness against UBC. Nevertheless, it has severe dose-limiting side effects, such as nephrotoxicity, among others. Since intracellular accumulation of platinum anticancer drugs is necessary for cytotoxicity, decreased uptake or enhanced efflux are the root causes of platinum resistance and response failure. Evidence suggests that genetic variations in any transporter involved in the entry or efflux of platinum drugs alter their kinetics and, to a significant extent, determine patients' responses to them. This review aims to consolidate and describe the major transporters and their polymorphic variants in relation to cisplatin-induced toxicities and resistance in UBC patients. We concluded that the efflux transporters ABCB1, ABCC2, SLC25A21, ATP7A, and the uptake transporter OCT2, as well as the organic anion uptake transporters OAT1 and OAT2, are linked to cisplatin accumulation, toxicity, and resistance in urinary bladder cancer patients. While suppressing the CTR1 gene's expression reduced cisplatin-induced nephrotoxicity and ototoxicity, inhibiting the expression of the MATE1 and MATE2-K genes has been shown to increase cisplatin's nephrotoxicity and resistance. The roles of ABCC5, ABCA8, ABCC10, ABCB10, ABCG1, ATP7B, ABCG2, and mitochondrial SLC25A10 in platinum-receiving urinary bladder cancer patients should be the subject of further investigation.

Evaluation of the gene encoding carnitine transporter (OCTN2/SLC22A5) expression in human breast cancer and its association with clinicopathological characteristics.

BACKGROUND: Fatty acid oxidation (FAO) is a major energy-generating process in the mitochondria and supports proliferation, growth, and survival of cancer cells. L-Carnitine is an essential co-factor for carrying long-chain fatty acids into the mitochondria. The entry of l-carnitine across cell membrane is regulated by OCTN2 (SLC22A5). Thus, it can plays a significant role in the mitochondrial fatty acid oxidation. This study aimed to evaluate the OCTN2 expression and its association with clinicopathological characteristics in breast cancer. METHODS: In this work, OCTN2 was examined in 54 pairs of fresh samples of breast cancer (BC) and adjacent noncancerous tissue using quantitative real-time polymerase chain reaction and immunohistochemistry (IHC). The IHC approach was also used to investigate the expression of additional clinicopathological features. RESULTS: The present research findings revealed that the relative expression of OCTN2 in BC tissues was substantially higher than the adjacent normal tissues. This up-regulation was correlated positively with tumor size and Ki-67 and negatively with the progesterone receptor (PR) status, providing evidence of the opposite effects of OCTN2 and PR on tumor development. CONCLUSION: The study shows that the OCTN2 expression in BC patients may be used as a prognostic biomarker and a tumor oncogene. As a result, it could be considered a possible therapeutic target. Nevertheless, the significance of the findings needs to be confirmed by further studies.

The impact of genetic variability in urate transporters on oxypurinol pharmacokinetics.

The genetic determinants of the allopurinol dose-concentration relationship have not been extensively studied. We aimed to clarify what factors, including genetic variation in urate transporters, influence oxypurinol pharmacokinetics (PKs). A population PK model for oxypurinol was developed with NONMEM (version 7.3). The influence of urate transporter genetic variants for ABCG2 (rs2231142 and rs10011796), SLC2A9/GLUT9 (rs11942223), SLC17A1/NPT1 (rs1183201), SLC22A12/URAT1 (rs3825018), SLC22A11/OAT4 (rs17300741), and ABCC4/MRP4 (rs4148500), as well as other participant factors on oxypurinol PKs was assessed. Data from 325 people with gout were available. The presence of the T allele for ABCG2 (rs2231142) and SLC17A1/NPT1 (rs1183201) was associated with a 24% and 22% increase in oxypurinol clearance, respectively, in univariate analysis. This effect was not significant in the multivariate analysis. In the final model, oxypurinol PKs were predicted by creatinine clearance, diuretic use, ethnicity, and body weight. We have found that genetic variability in the transporters examined does not appear to influence oxypurinol PKs.

A novel mutation in a patient with familial renal hypouricemia type 2.

INTRODUCTION: Hypouricemia may be caused by disorders leading to decreased UA production, oxidation of UA to allantoin by drugs or increased renal tubular loss of filtered UA, renal hypouricemia (RHUC). RHUC may be resulted from familial or acquired disorders. Familial RHUC cases are classified according to the gene affected as type 1 (SLC22A12 gene) and type 2 (SLC2A9). Clinical importance of RHUC entity is mainly determined by emerging of acute kidney injury (AKI) after strenuous exercise and urolithiasis. CASE PRESENTATION: Here, we report a case of RHUC with increased fractional excretion of uric acid value of more than 100%, serum uric acid level of nearly zero, and exercise-induced AKI episodes clinically and a new unpublished homozygous (biallelic) mutation of c.1419+2T>G (IVS11+2T>G) in the SLC2A9 gene genetically for the first time to our knowledge. CONCLUSION: Clinicians should be aware of this rare entity defined as hereditary RHUC in order to provide long term renoprotection by advisements like simple precautions such as avoiding severe exercises.

Nomogram Models Based on the Gene Expression in Prediction of Breast Cancer Bone Metastasis.

Objective: The aim of this study is to design a weighted co-expression network and build gene expression signature-based nomogram (GESBN) models for predicting the likelihood of bone metastasis in breast cancer (BC) patients. Methods: Dataset GSE124647 was used as a training set, while GSE16446, GSE45255, and GSE14020 were taken as validation sets. In the training cohort, the limma package in R was adopted to obtain differentially expressed genes (DEGs) between BC nonbone metastasis and bone metastasis patients, which were used for functional enrichment analysis. After weighted co-expression network analysis (WGCNA), univariate Cox regression and Kaplan-Meier plotter analyses were performed to screen potential prognosis-related genes. Then, GESBN models were constructed and evaluated. The prognostic value of the GESBN models was investigated in the GSE124647 dataset, which was validated in GSE16446 and GSE45255 datasets. Further, the expression levels of genes in the models were explored in the training set, which was validated in GSE14020. Finally, the expression and prognostic value of hub genes in BC were explored. Results: A total of 1858 DEGs were obtained. The WGCNA result showed that the blue module was most significantly related to bone metastasis and prognosis. After survival analyses, GAJ1, SLC24A3, ITGBL1, and SLC44A1 were subjected to construct a GESBN model for overall survival (OS). While GJA1, IGFBP6, MDFI, TGFBI, ANXA2, and SLC24A3 were subjected to build a GESBN model for progression-free survival (PFS). Kaplan-Meier plotter and receiver operating characteristic analyses presented the reliable prediction ability of the models. Cox regression analysis further revealed that GESBN models were independent prognostic predictors for OS and PFS in BC patients. Besides, GJA1, IGFBP6, ITGBL1, SLC44A1, and TGFBI expressions were significantly different between the two groups in GSE124647 and GSE14020. The hub genes had a significant impact on patient prognosis. Conclusion: Both the four-gene signature and six-gene signature could accurately predict patient prognosis, which may provide novel treatment insights for BC bone metastasis.