RESUMEN

Autosomal recessive type 2 primary hypertrophic osteoarthropathy (PHOAR2) and chronic enteropathy associated with SLCO2A1 (CEAS) are two entities caused by pathogenic variants (PVs) in the SLCO2A1 gene that can coexist or occur independently from one another. We report two cases of PHOAR2 in Mexico with concomitant CEAS and conducted a review of the literature of the reported cases of PHOAR2 and/or CEAS to analyze the relationship between their genotype and phenotype presentation. The patients from our Institution with classical PHOAR2 phenotype and CEAS, harbored SLCO2A1 c.547G > A and c.1768del variants. We reviewed 232 cases, of which 86.6% were of Asian origin, and identified 109 different variants in SLCO2A1. Intron 7, exon 13, and exon 4 were predominantly affected. The two most common PVs were c.940 + 1G > A and c.1807C > T. We found a statistically significant association between SLCO2A1 variants located in intron 7, exons 12, and 13 and the development of CEAS. Missense variants were more frequent in isolated PHOAR2, while a greater proportion of protein-truncating variants (PTVs) were found in CEAS. Further investigation is imperative to elucidate the underlying pathophysiological mechanisms associated with CEAS, thereby facilitating the identification of effective therapeutic interventions.

Asunto(s)

Transportadores de Anión Orgánico , Osteoartropatía Hipertrófica Primaria , Humanos , Osteoartropatía Hipertrófica Primaria/diagnóstico , Osteoartropatía Hipertrófica Primaria/genética , Transportadores de Anión Orgánico/genética , Genotipo , Fenotipo , Mutación Missense

RESUMEN

The activity of the membrane transporters organic anion-transporting polypeptide 1B1 (OATP1B1) & breast cancer resistance protein (BCRP) (rosuvastatin) and P-glycoprotein (P-gp) (fexofenadine) was evaluated in patients with chronic hepatitis C virus (HCV) infection (n = 28), genotypes 1 and 3, investigated before the treatment with direct-acting antiviral agents (Phase 1) and up to 30 days after the assessment of the virologic response (Phase 2). Participants allocated in Groups 1 (n = 15; F0/F1 and F2, mild to moderate liver fibrosis) and 2 (n = 13; F3 and F4, advanced course of liver fibrosis/cirrhosis) received in both phases fexofenadine (10 mg) and rosuvastatin (2 mg). OATP1B1 & BCRP activity (rosuvastatin area under the plasma concentration-time curve of rosuvastatin from time zero to infinity (AUC0-∞ )) was reduced in Groups 1 and 2, respectively, by 25% (ratio 0.75 (0.53-0.82), P < 0.01) and 31% (ratio 0.69 (0.46-0.85), P < 0.05) in Phase 1 compared with Phase 2. OATP1B1 & BCRP activity was reduced in Phases 1 and 2, respectively, by 49% (median ratio 1.51 (1.17-2.20), P < 0.05) and 61% (ratio 1.39 (1.16-2.02), P < 0.01) in Group 2 compared with Group 1. P-gp activity (fexofenadine AUC0-∞ ) was also reduced in Phase 1 compared with Phase 2 (ratio Phase2/Phase1 0.79 (0.66-0.96) in Group 1 and 0.81 (0.69-0.96) in Group 2) as well as in Group 2 compared with Group 1 in both Phases (ratio Group2/Group1 1.47 (1.08-2.01) in Phase 1 and 1.51 (1.10-2.07) in Phase 2). Thus, clinicians administering OATP1B1 & BCRP and P-gp substrates with low therapeutic indexes should consider the evolution of the treatment and the stage of HCV infection.

Asunto(s)

Hepatitis C Crónica , Transportadores de Anión Orgánico , Humanos , Proteínas de Transporte de Membrana/metabolismo , Rosuvastatina Cálcica , Hepatitis C Crónica/tratamiento farmacológico , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Glicoproteínas de Membrana/metabolismo , Antivirales/uso terapéutico , Interacciones Farmacológicas , Proteínas de Neoplasias/metabolismo , Transportadores de Anión Orgánico/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP , Cirrosis Hepática/tratamiento farmacológico

RESUMEN

This study evaluates the influence of pregnancy and HIV infection in conjunction with the use of raltegravir, lamivudine, and tenofovir disoproxil fumarate (combined antiretroviral therapy [cART]) on intestinal P-glycoprotein (P-gp) and hepatic organic anion transporter polypeptide (OATP) 1B1/1B3 and/or breast cancer resistance protein (BCRP) drug transporter activity using rosuvastatin (OATP1B/BCRP) and fexofenadine (P-gp) probes. Single oral doses of 5-mg rosuvastatin and 60-mg fexofenadine were administered to women living with HIV under cART in the third trimester of gestation (n = 15) and postpartum period (n = 10). A control group of 12 healthy nonpregnant women also was investigated. Pharmacokinetic parameters were estimated by using a noncompartmental method and evaluated by t test (P < .05). The rosuvastatin area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUC0-last ) value was higher in the third trimester of pregnancy (19.5 [95%CI, 16.8-22.3] ng • h/mL] when compared to postpartum (13.3 [95%CI, 9.3-17.5] ng • h/mL), while the fexofenadine AUC0-last values did not differ between the third trimester of pregnancy (738.0 [95%CI, 611.4-864.6] ng • h/mL) and postpartum period (874.9 [95%CI, 408.2-1342.0] ng• h/mL). The rosuvastatin AUC0-last values did not differ between healthy nonpregnant women (13.8 [95%CI, 10.0-17.6] ng • h/mL) and women living with HIV in the postpartum period (13.3 [95%CI, 9.3-17.5] ng • h/mL), and the fexofenadine AUC0-last values did not differ between the 2 investigated groups (603.6 [95%CI, 467.5-739.7] ng • h/mL vs 874.9 [95%CI, 408.2-1342.0] ng • h/mL). It is suggested that gestation inhibits the hepatic OATP1B1/1B3 and/or BCRP activity but does not alter intestinal P-gp activity. The influence of HIV infection in conjunction with use of cART on OATP1B/BCRP and intestinal P-gp activity was not observed.

Asunto(s)

Neoplasias de la Mama , Infecciones por VIH , Transportadores de Anión Orgánico , Humanos , Femenino , Embarazo , Rosuvastatina Cálcica/farmacocinética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Mujeres Embarazadas , Infecciones por VIH/tratamiento farmacológico , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Interacciones Farmacológicas , Proteínas de Neoplasias/metabolismo

RESUMEN

The organic anion transporting polypeptide family member (OATP) 1B3 is a hepatic uptake transporter that has a broad substrate recognition and plays a significant role in regulating elimination of endogenous biomolecules or xenobiotics. OATP1B3 works in tandem with OATP1B1, with which it shares approximately 80% sequence homology and a high degree of substrate overlap. Despite some substrates being recognized solely by OATP1B3, its ability to compensate for loss of OATP1B1-mediated elimination and recognition by regulatory agencies, little is known about OATP1B3 regulatory factors and how they are involved with drug-drug interaction. It was recently discovered that OATP1B1 function is mediated by the activity of a particular tyrosine kinase that is sensitive to a variety of tyrosine kinase inhibitors (TKIs). This study reports that OATP1B3 is similarly regulated, as at least 50% of its activity is reduced by 20 US Food and Drug Administration -approved TKIs. Nilotinib was assessed as the most potent OATP1B3 inhibitor among the investigated TKIs, which can occur at clinically relevant concentrations and acted predominantly through noncompetitive inhibition without impacting membrane expression. Finally, OATP1B3 function was determined to be sensitive to the knockdown of the Lck/Yes novel tyrosine kinase that is sensitive to nilotinib and has been previously implicated in mediating OATP1B1 activity. Collectively, our findings identify tyrosine kinase activity as a major regulator of OATP1B3 function which is sensitive to kinase inhibition. Given that OATP1B1 is similarly regulated, simultaneous disruption of these transporters can have drastic effects on systemic drug concentrations, which would promote adverse events. SIGNIFICANCE STATEMENT: The organic anion transporting polypeptide family member (OATP) 1B3 is a facilitator of hepatic drug elimination, although much is unknown of how OATP1B3 activity is mediated, or how such regulators contribute to drug-drug interactions. This study reports that OATP1B3 activity is dependent on the Lck/Yes novel tyrosine kinase, which is sensitive to numerous tyrosine kinase inhibitors. These findings provide insight into the occurrence of many clinical drug-drug interactions, and a rationale for future study of tyrosine kinases regulating drug disposition.

Asunto(s)

Transportadores de Anión Orgánico , Proteínas Tirosina Quinasas , Interacciones Farmacológicas , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Transportadores de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/metabolismo , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos/metabolismo

RESUMEN

Background: Hyperuricemia is a pathological condition associated with risk factors of cardiovascular disease. In this study, three genetic polymorphisms were genotyped as predisposing factors of hyperuricemia. Methods: A total of 860 Mexicans between 18 and 25 years of age were genotyped for the ABCG2 (rs2231142), SLC22A12 (rs476037), and XDH (rs1042039) polymorphisms, as predisposing factors of hyperuricemia. Biochemical parameters were measured by spectrophotometry, while genetic polymorphisms were analyzed by real-time PCR. An analysis of the risk of hyperuricemia in relation to the variables studied was carried out using a logistic regression. Results: Male sex, being overweight or obese, having hypercholesterolemia or having hypertriglyceridemia were factors associated with hyperuricemia ( p ≤ 0.05). The ABCG2 polymorphism was associated with hyperuricemia (OR = 2.43, 95% CI: 1.41-4.17, p = 0.001) and hypercholesterolemia (OR = 4.89, 95% CI: 1.54-15.48, p = 0.003), employing a dominant model, but only in male participants. Conclusions: The ABCG2 (rs2231142) polymorphism increases the risk of hyperuricemia and hypercholesterolemia in young Mexican males.

Asunto(s)

Hipercolesterolemia , Hiperuricemia , Transportadores de Anión Orgánico , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Predisposición Genética a la Enfermedad , Humanos , Hipercolesterolemia/genética , Hiperuricemia/genética , Masculino , Proteínas de Neoplasias/genética , Transportadores de Anión Orgánico/genética , Proteínas de Transporte de Catión Orgánico/genética , Polimorfismo de Nucleótido Simple , Ácido Úrico , Adulto Joven

RESUMEN

Although structurally related, mitochondrial carrier family (MCF) proteins catalyze the specific transport of a range of diverse substrates including nucleotides, amino acids, dicarboxylates, tricarboxylates, cofactors, vitamins, phosphate and H+. Despite their name, they do not, however, always localize to the mitochondria, with plasma membrane, peroxisomal, chloroplast and thylakoid and endoplasmic reticulum localizations also being reported. The existence of plastid-specific MCF proteins is suggestive that the evolution of these proteins occurred after the separation of the green lineage. That said, plant-specific MCF proteins are not all plastid-localized, with members also situated at the endoplasmic reticulum and plasma membrane. While by no means yet comprehensive, the in vivo function of a wide range of these transporters is carried out here, and we discuss the employment of genetic variants of the MCF as a means to provide insight into their in vivo function complementary to that obtained from studies following their reconstitution into liposomes.

Asunto(s)

Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Proteínas de Plantas/metabolismo , Sistemas de Transporte de Aminoácidos/genética , Sistemas de Transporte de Aminoácidos/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Coenzima A/metabolismo , Regulación de la Expresión Génica de las Plantas , Hierro/metabolismo , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/genética , Proteínas Desacopladoras Mitocondriales/genética , Proteínas Desacopladoras Mitocondriales/metabolismo , Modelos Biológicos , NAD/metabolismo , Transportadores de Anión Orgánico/genética , Transportadores de Anión Orgánico/metabolismo , Proteínas de Transporte de Fosfato/genética , Proteínas de Transporte de Fosfato/metabolismo , Proteínas de Plantas/genética

RESUMEN

The relationship of uric acid with macrophages has not been fully elucidated. We investigated the effect of uric acid on the proinflammatory ability of human macrophages and then examined the possible molecular mechanism involved. Primary human monocytes were differentiated into macrophages for subsequent exposure to 0, 0.23, 0.45, or 0.9 mmol/L uric acid for 12 h, in the presence or absence of 1 mmol/L probenecid. Flow cytometry was used to measure proinflammatory marker production and phagocytic activity that was quantified as a percentage of GFP-labeled Escherichia coli positive macrophages. qPCR was used to measure the macrophage expression of the urate anion transporter 1 (URAT1). As compared to control cells, the production of tumor necrosis factor-alpha (TNF-alpha), toll-like receptor 4 (TLR4), and cluster of differentiation (CD) 11c was significantly increased by uric acid. In contrast, macrophages expressing CD206, CX3C-motif chemokine receptor 1 (CX3CR1), and C-C chemokine receptor type 2 (CCR2) were significantly reduced. Uric acid progressively increased macrophage phagocytic activity and downregulated URAT1 expression. Probenecid-a non-specific blocker of URAT1-dependent uric acid transport-inhibited both proinflammatory cytokine production and phagocytic activity in macrophages that were exposed to uric acid. These results suggest that uric acid has direct proinflammatory effects on macrophages possibly via URAT1.

Asunto(s)

Escherichia coli/metabolismo , Mediadores de Inflamación/metabolismo , Inflamación/patología , Macrófagos/patología , Transportadores de Anión Orgánico/metabolismo , Proteínas de Transporte de Catión Orgánico/metabolismo , Fagocitosis/efectos de los fármacos , Ácido Úrico/toxicidad , Adolescente , Adulto , Receptor 1 de Quimiocinas CX3C/metabolismo , Células Cultivadas , Humanos , Interleucina-1beta/metabolismo , Lectinas Tipo C/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Receptor de Manosa , Lectinas de Unión a Manosa/metabolismo , Probenecid/farmacología , Receptores CCR2/metabolismo , Receptores de Superficie Celular/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Adulto Joven

RESUMEN

BACKGROUND: Benzbromarone is a uricosuric drug that has been used in the treatment of gout over the last 30 years. Due to its potent inhibition of the dominant apical (luminal) urate exchanger in the human proximal tubule URAT1, it reduces the urate reabsorption, diminishing serum urate levels and therefore preventing gout flares. Through several clinical trials, Benzbromarone has been proved effective and safe, inclusive in patients with chronic kidney disease and as combination therapy with allopurinol. Due to hepatotoxicity reports, it was withdrawn from the European market by the manufacturer, however many authors have questioned the product's withdrawal due to a lack of clinical evidence in order to support its hepatotoxicity. Benzbromarone is still available in several European countries, New Zealand, Brazil and several other countries. Despite the product's marketing over more than 20 years after the first hepatotoxicity reports, we have found only five reports in our literature search, and no prospective or retrospective study correlating hepatotoxicity with benzbromarone use. SHORT CONCLUSION: Benzbromarone is a safe and effective molecule for the treatment of gout. However, due to in vitro and in vivo data related to hepatotoxicity, it is prudent to prescribe it with some caution, especially for patients with an already known liver condition.

Asunto(s)

Benzbromarona/uso terapéutico , Gota/tratamiento farmacológico , Uricosúricos/uso terapéutico , Benzbromarona/efectos adversos , Benzbromarona/metabolismo , Citocromo P-450 CYP2C9/metabolismo , Humanos , Técnicas In Vitro , Hígado/efectos de los fármacos , Hígado/metabolismo , Mitocondrias Hepáticas/efectos de los fármacos , Modelos Animales , Transportadores de Anión Orgánico/antagonistas & inhibidores , Proteínas de Transporte de Catión Orgánico/antagonistas & inhibidores , Retirada de Medicamento por Seguridad , Brote de los Síntomas , Uricosúricos/efectos adversos , Uricosúricos/metabolismo

Asunto(s)

Variación Genética/genética , Transportadores de Anión Orgánico/genética , Osteoartropatía Hipertrófica Primaria/diagnóstico , Osteoartropatía Hipertrófica Primaria/genética , Humanos , Masculino , México , Adulto Joven

RESUMEN

AIM: The association of transporters gene polymorphisms with chloroquine/primaquine malaria treatment response was investigated in a Brazilian population. PATIENTS & METHODS: Totally, 164 Plasmodium vivax malaria infected patients were included. Generalized estimating equations were performed to determine gene influences on parasitemia and/or gametocytemia clearance over treatment time. RESULTS: Significant interaction between SLCO2B1 genotypes and treatment over time for parasitemia clearance rate on day 2 were observed (p FDR = 0.002). SLCO1A2 and SLCO1B1 gene treatment over time interactions were associated with gametocytemia clearance rate (p FDR = 0.018 and p FDR = 0.024). ABCB1, ABCC4 and SLCO1B3 were not associated with treatment response. CONCLUSION: The present work presents the first pharmacogenetic report of an association between chloroquine/primaquine responses with OATP transporters.

Asunto(s)

Cloroquina/uso terapéutico , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Malaria Vivax/genética , Transportadores de Anión Orgánico/genética , Polimorfismo Genético/genética , Primaquina/uso terapéutico , Adulto , Antimaláricos/uso terapéutico , Brasil , Quimioterapia Combinada/métodos , Femenino , Genotipo , Humanos , Malaria Vivax/tratamiento farmacológico , Masculino , Parasitemia/tratamiento farmacológico , Parasitemia/genética , Plasmodium vivax/efectos de los fármacos , Resultado del Tratamiento

RESUMEN

Malate is a central metabolite involved in a multiplicity of plant metabolic pathways, being associated with mitochondrial metabolism and playing significant roles in stomatal movements. Vacuolar malate transport has been characterized at the molecular level and is performed by at least one carrier protein and two channels in Arabidopsis (Arabidopsis thaliana) vacuoles. The absence of the Arabidopsis tonoplast Dicarboxylate Transporter (tDT) in the tdt knockout mutant was associated previously with an impaired accumulation of malate and fumarate in leaves. Here, we investigated the consequences of this lower accumulation on stomatal behavior and photosynthetic capacity as well as its putative metabolic impacts. Neither the stomatal conductance nor the kinetic responses to dark, light, or high CO2 were highly affected in tdt plants. In addition, we did not observe any impact on stomatal aperture following incubation with abscisic acid, malate, or citrate. Furthermore, an effect on photosynthetic capacity was not observed in the mutant lines. However, leaf mitochondrial metabolism was affected in the tdt plants. Levels of the intermediates of the tricarboxylic acid cycle were altered, and increases in both light and dark respiration were observed. We conclude that manipulation of the tonoplastic organic acid transporter impacted mitochondrial metabolism, while the overall stomatal and photosynthetic capacity were unaffected.

Asunto(s)

Proteínas de Arabidopsis/genética , Arabidopsis/metabolismo , Fumaratos/metabolismo , Malatos/metabolismo , Mutación/genética , Transportadores de Anión Orgánico/genética , Estomas de Plantas/fisiología , Vacuolas/metabolismo , Aminoácidos/metabolismo , Arabidopsis/crecimiento & desarrollo , Proteínas de Arabidopsis/metabolismo , Respiración de la Célula , Clorofila/metabolismo , Clorofila A , Ciclo del Ácido Cítrico , Fluorescencia , Técnicas de Inactivación de Genes , Metaboloma , Transportadores de Anión Orgánico/metabolismo , Fotoperiodo , Fotosíntesis , Estomas de Plantas/citología , Almidón/metabolismo

RESUMEN

PURPOSE: Rocuronium (ROC) is a neuromuscular blocker mainly eliminated by biliary excretion dependent on organic anion transporting polypeptide 1A2 (OATP1A2) hepatocellular uptake. However, the influence of SLCO1A2 (gene encoding OATP1A2) genetic polymorphism on ROC pharmacokinetics was never described before. The objective of this work was to evaluate the influence of genetic polymorphisms of SLCO1A2 on the pharmacokinetics of rocuronium (ROC). METHODS: Patients undergoing elective surgeries under general anesthesia using rocuronium as a neuromuscular blocker were genotyped for SLCO1A2 polymorphisms in the coding region (41A>G, 382A>T, 404A>T, 502C>T, 516A>C, 559G>A, 830C>A, and 833delA) and in the promoter region (-1105G>A, -1032G>A, -715T>C, -361G>A, and -189_-188insA). Rocuronium pharmacokinetic parameters were estimated by non-compartmental analysis. RESULTS: None of the patients had heterozygous or homozygous variant of 404A>T, 382A>T, 502C>T, 833delA, 830C>A, 41A>G, and -715T>C. A linkage disequilibrium was found between -1105G>A and -1032G>A genotypes. Patients genotyped as -A or AA (n = 17) for SLCO1A2 -189_-188InsA showed reduced total clearance of ROC compared to patients genotyped as -/- (n = 13) (151.6 vs 207.1 mL/min, p ≤ 0.05). The pharmacokinetics parameters of ROC were not significantly different between other SLCO1A2 genotypes. CONCLUSION: SLCO1A2 -189_-188InsA polymorphism is related to the reduced clearance of rocuronium in patients submitted to elective surgeries under general anesthesia. TRIAL REGISTRATION: NCT 02399397 ( ClinicalTrials.gov ).

Asunto(s)

Androstanoles/farmacocinética , Fármacos Neuromusculares no Despolarizantes/farmacocinética , Transportadores de Anión Orgánico/genética , Adulto , Anciano , Androstanoles/sangre , Procedimientos Quirúrgicos Electivos , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Fármacos Neuromusculares no Despolarizantes/sangre , Polimorfismo de Nucleótido Simple , Rocuronio

RESUMEN

Adverse reactions are the main cause of treatment discontinuation among HIV+ individuals. Genes related to drug absorption, distribution, metabolism and excretion (ADME) influence drug bioavailability and treatment response. We have investigated the association between single nucleotide polymorphisms (SNPs) in 29 ADME genes and intolerance to therapy in a case-control study including 764 individuals. Results showed that 15 SNPs were associated with intolerance to nucleoside and 11 to non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs), and 8 to protease inhibitors (PIs) containing regimens under alpha = 0.05. After Bonferroni adjustment, two associations remained statistically significant. SNP rs2712816, at SLCO2B1 was associated to intolerance to NRTIs (ORGA/AA = 2.37; p = 0.0001), while rs4148396, at ABCC2, conferred risk of intolerance to PIs containing regimens (ORCT/TT = 2.64; p = 0.00009). Accordingly, haplotypes carrying rs2712816A and rs4148396T alleles were also associated to risk of intolerance to NRTIs and PIs, respectively. Our data reinforce the role of drug transporters in response to HIV therapy and may contribute to a future development of personalized therapies.

Asunto(s)

Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/genética , Seropositividad para VIH/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Transportadores de Anión Orgánico/genética , Polimorfismo de Nucleótido Simple , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Alelos , Estudios de Casos y Controles , Femenino , Infecciones por VIH/tratamiento farmacológico , Seropositividad para VIH/tratamiento farmacológico , VIH-1 , Haplotipos , Humanos , Masculino , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Farmacogenética

RESUMEN

In this review we discuss the structure and functions of the aspartate/glutamate carriers (AGC1-aralar and AGC2-citrin). Those proteins supply the aspartate synthesized within mitochondrial matrix to the cytosol in exchange for glutamate and a proton. A structure of an AGC carrier is not available yet but comparative 3D models were proposed. Moreover, transport assays performed by using the recombinant AGC1 and AGC2, reconstituted into liposome vesicles, allowed to explore the kinetics of those carriers and to reveal their specific transport properties. AGCs participate to a wide range of cellular functions, as the control of mitochondrial respiration, calcium signaling and antioxydant defenses. AGC1 might also play peculiar tissue-specific functions, as it was found to participate to cell-to-cell metabolic symbiosis in the retina. On the other hand, AGC1 is involved in the glutamate-mediated excitotoxicity in neurons and AGC gene or protein alterations were discovered in rare human diseases. Accordingly, a mice model of AGC1 gene knock-out presented with growth delay and generalized tremor, with myelinisation defects. More recently, AGC was proposed to play a crucial role in tumor metabolism as observed from metabolomic studies showing that the asparate exported from the mitochondrion by AGC1 is employed in the regeneration of cytosolic glutathione. Therefore, given the central role of AGCs in cell metabolism and human pathology, drug screening are now being developed to identify pharmacological modulators of those carriers. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou.

Asunto(s)

Ácido Aspártico/metabolismo , Proteínas de Unión al Calcio/fisiología , Ácido Glutámico/metabolismo , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/fisiología , Transportadores de Anión Orgánico/fisiología , Secuencia de Aminoácidos , Animales , Transporte Biológico Activo/efectos de los fármacos , Proteínas de Unión al Calcio/antagonistas & inhibidores , Proteínas de Unión al Calcio/genética , Bovinos , Secuencia de Consenso , Humanos , Malatos/metabolismo , Ratones , Proteínas de Transporte de Membrana Mitocondrial/antagonistas & inhibidores , Proteínas de Transporte de Membrana Mitocondrial/deficiencia , Proteínas de Transporte de Membrana Mitocondrial/genética , Modelos Moleculares , NAD/metabolismo , Proteínas de Neoplasias/fisiología , Especificidad de Órganos , Transportadores de Anión Orgánico/antagonistas & inhibidores , Transportadores de Anión Orgánico/genética , Oxidación-Reducción , Conformación Proteica , Alineación de Secuencia , Homología de Secuencia de Aminoácido

RESUMEN

KEY MESSAGE: TaALMT1 and TaMATE1B promoter alleles are highly correlated with wheat growth in acidic soil with a high concentration of toxic aluminium. The aluminium (Al(3+)) resistance of 338 wheat genotypes with different geographic origins was correlated with morphological traits and TaALMT1 and TaMATE1B alleles. Both of these genes encode malate and citrate transporters associated with Al(3+) resistance mechanisms in wheat. Based on comparisons with the sensitive and resistant controls, the relative root growth was evaluated in hydroponic experiments and the plant performance was visually accessed in the field. The correlation between Al(3+) tolerance in the hydroponic and field tests was moderate (r = 0.56, P < 0.001). Higher selection pressure was observed in the field because a smaller number of genotypes was classified as resistant. The combination between the six TaALMT1 alleles and the two TaMATE1B promoters allowed the identification of 11 haplotypes that showed a high (r = 0.71, P < 0.001) correlation with Al(3+) resistance in the field, with the TaALMT1 alleles accounting for most of the correlation. The Brazilian wheat genotypes presented the best performance in soil, including eight cultivars with promoters usually associated with Al(3+) resistance and another six genotypes classified as moderately resistant but containing alleles usually associated with Al(3+) sensitivity. Although an increase in favourable alleles was observed over the past few decades, the average Al(3+) resistance in the field was not significantly different from that of older cultivars. The ease identification of the TaALMT1 and TaMATE1B alleles and their higher association with Al(3+) resistance along with the best genotypes identified here may be used for wheat-breeding programmes interested in increasing wheat Al(3+) resistance.

Asunto(s)

Aluminio/toxicidad , Transportadores de Anión Orgánico/genética , Proteínas de Plantas/genética , Suelo/química , Triticum/genética , Ácidos/química , Alelos , Proteínas Portadoras/genética , ADN de Plantas/genética , Genotipo , Haplotipos , Hidroponía , Regiones Promotoras Genéticas , Contaminantes del Suelo/toxicidad

RESUMEN

OBJECTIVES: To ascertain a molecular genetic diagnosis for subjects with neonatal/infantile intrahepatic cholestasis (NIIC) by the use of next-generation sequencing (NGS) and to perform a genotype-phenotype correlation. STUDY DESIGN: We recruited Japanese subjects with NIIC who had no definitive molecular genetic diagnosis. We developed a diagnostic custom panel of 18 genes, and the amplicon library was sequenced via NGS. We then compared clinical data between the molecular genetically confirmed subjects with NIIC. RESULTS: We analyzed 109 patients with NIIC ("genetic cholestasis," 31 subjects; "unknown with complications" such as prematurity, 46 subjects; "unknown without complications," 32 subjects), and a molecular genetic diagnosis was made for 28 subjects (26%). The rate of positive molecular genetic diagnosis in each category was 22 of 31 (71%) for the "genetic cholestasis" group, 2 of 46 (4.3%) for the "unknown with complications" group, and 4 of 32 (12.5%) for the "unknown without complications" group. The grouping of the molecular diagnoses in the group with genetic cholestasis was as follows: 12 with Alagille syndrome, 5 with neonatal Dubin-Johnson syndrome, 5 with neonatal intrahepatic cholestasis caused by citrin deficiency, and 6 with progressive familial intrahepatic cholestasis or benign recurrent intrahepatic cholestasis with low gamma-glutamyl transpeptidase levels. Several clinical datasets, including age of onset, direct bilirubin, and aminotransferases, were significantly different between the disorders confirmed using molecular genetic diagnosis. CONCLUSION: Targeted NGS can be used for molecular genetic diagnosis in subjects with NIIC. Clinical diagnosis should be accordingly redefined in the view of molecular genetic findings.

Asunto(s)

Colestasis Intrahepática/diagnóstico , Colestasis Intrahepática/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Síndrome de Alagille/diagnóstico , Síndrome de Alagille/genética , Bilirrubina/sangre , Proteínas de Unión al Calcio/deficiencia , Aberraciones Cromosómicas , Exones , Femenino , Eliminación de Gen , Estudios de Asociación Genética , Genómica , Humanos , Lactante , Recién Nacido , Japón , Ictericia Idiopática Crónica/diagnóstico , Ictericia Idiopática Crónica/genética , Masculino , Biología Molecular , Transportadores de Anión Orgánico/deficiencia , gamma-Glutamiltransferasa/genética

Asunto(s)

Humanos , Masculino , Femenino , Anciano , Anciano de 80 o más Años , Claritromicina/efectos adversos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Inhibidores del Citocromo P-450 CYP3A/efectos adversos , Pirimidinas/metabolismo , Pirimidinas/uso terapéutico , Pirimidinas/farmacocinética , Rabdomiólisis/inducido químicamente , Sulfonamidas/metabolismo , Sulfonamidas/uso terapéutico , Sulfonamidas/farmacocinética , Ácidos Grasos Monoinsaturados/metabolismo , Ácidos Grasos Monoinsaturados/uso terapéutico , Ácidos Grasos Monoinsaturados/farmacocinética , Pravastatina/metabolismo , Pravastatina/uso terapéutico , Pravastatina/farmacocinética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/metabolismo , Transportadores de Anión Orgánico , Transportadores de Anión Orgánico Sodio-Independiente/antagonistas & inhibidores , Transportador 1 de Anión Orgánico Específico del Hígado , Interacciones Farmacológicas , Lesión Renal Aguda/inducido químicamente , Rosuvastatina Cálcica , Fluorobencenos/metabolismo , Fluorobencenos/uso terapéutico , Fluorobencenos/farmacocinética , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos , Fluvastatina , Hiperpotasemia/inducido químicamente , Indoles/metabolismo , Indoles/uso terapéutico , Indoles/farmacocinética

RESUMEN

Intracrinology mechanism involves the metabolism of steroids in peripheral tissues, such as DHEA, to molecules with estrogenic or androgenic activity. Proliferation rate of endometria from Polycystic Ovary Syndrome women (PCOS) is increased, favoring hyperplasia development. Besides, in endometria from PCOS-women the synthesis of androst-5-ene-3ß,17ß-diol (androstenediol), an estrogenic molecule, is enhanced concomitantly to increased cellular proliferation. DHEA, the major intracrinological precursor, circulates mainly in its sulfated form and requires transporters for cell intake, that belong to the families of organic anion transporting polypeptides (OATP) and organic anion transporters (OAT). The aim of this study was to determine protein levels and activity of sulfated steroid transporters OATP2B1, OATP3A1, OATP4A1 and OAT4 in endometria from control and PCOS-women and to evaluate the activity of the enzyme 3ß-HSD. Levels of transporters were done by RT-PCR (OAT4 only) and Western-blot (WB). Additionally, in primary culture cells stimulated with steroids, protein levels by WB and uptake of tritiated DHEAS, were evaluated; 3ß-HSD activity was assessed using radiolabel substrate. PCOS-endometrium had higher levels of OATP2B1 and OATP4A1 than CE (p<0.05); decreased OATP4A1 levels were found in androstenediol or testosterone-stimulated cells. Accordingly, the entry of DHEAS to cells was lower in cells stimulated with testosterone (p<0.05); 3ß-HSD-activity was similar in control and PCOS-endometria. Therefore, this study describes that steroids can modulate the expression and activity of transporters of OATPs-family in human endometria and that some transporter levels are increased in PCOS-endometria, suggesting a potential role in the pathogenesis of endometrial hyperplasia of these patients.

Asunto(s)

3-Hidroxiesteroide Deshidrogenasas/metabolismo , Endometrio/metabolismo , Transportadores de Anión Orgánico/metabolismo , Síndrome del Ovario Poliquístico/metabolismo , Adulto , Células Cultivadas , Endometrio/enzimología , Activación Enzimática , Femenino , Perfilación de la Expresión Génica , Humanos , Transportadores de Anión Orgánico/biosíntesis , Transportadores de Anión Orgánico/genética , Síndrome del Ovario Poliquístico/enzimología , Síndrome del Ovario Poliquístico/genética

RESUMEN

The use of statins as the preferred lipid-lowering therapy has clearly demonstrated its efficacy in the treatment of hypercholesterolemia, reducing also the risk of coronary events and cardiovascular disease mortality. In this study, we assessed single nucleotide polymorphisms (SNPs) in the SLCO1B1 gene and their effect on atorvastatin response. We included 129 Chilean hypercholesterolemic patients undergoing 10 mg/day of atorvastatin therapy during 4 weeks. Lipid profile was determined before and after drug administration. Genotyping of SLCO1B1 rs4149056 (c.521T>C) SNP was performed with allele-specific polymerase chain reaction, whilst polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for genotyping the SLCO1B1 rs2306283 (c.388A>G) variant. After statin therapy, concentrations of TC, LDL-C and TG had a decrease from baseline (p < 0.05). Also, HDL-C levels increased (p < 0.05). Minor allele frequencies for the rs2306283 and rs4149056 variants were 0.547 and 0.136, respectively. LDL-C response to atorvastatin was not associated with the SLCO1B1 rs4149056 nor the rs2306283 polymorphisms (p > 0.05). However, the latter SNP was associated with HDL-C variability after atorvastatin medication (p = 0.02). This study indicates that LDL-C reduction following atorvastatin therapy is not influenced by the SNPs evaluated. In addition, the polymorphism rs2306283 at the SLCO1B1 gene determines greater HDL-C concentrations in response to atorvastatin medication in Chilean hypercholesterolemic subjects.

Asunto(s)

HDL-Colesterol/sangre , Hipercolesterolemia/sangre , Hipercolesterolemia/genética , Transportadores de Anión Orgánico/genética , Polimorfismo de Nucleótido Simple , Anciano , Atorvastatina/uso terapéutico , Chile/epidemiología , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipercolesterolemia/tratamiento farmacológico , Hipercolesterolemia/epidemiología , Lípidos/sangre , Transportador 1 de Anión Orgánico Específico del Hígado , Masculino , Persona de Mediana Edad , Farmacogenética , Vigilancia en Salud Pública , Resultado del Tratamiento

RESUMEN

Cisplatin is a commonly used chemotherapeutic agent. Its main side-effect is nephrotoxicity. It was reported that the organic anion transporter 5 (Oat5) urinary excretion is elevated, implying renal perturbation, when no modifications of traditional markers of renal damage are still observed in cisplatin-induced acute kidney injury (AKI). It was also demonstrated that Oat5 is excreted in urine by the exosomal pathway. This study was designated to demonstrate the specific response of the urinary excretion of exosomal Oat5 to kidney injury independently of other cisplatin toxic effects, in order to strengthen Oat5 urinary levels as a specific biomarker of AKI. To accomplish that aim, we evaluated if urinary excretion of exosomal Oat5 returns to its basal levels when cisplatin renal damage is prevented by the coadministration of the renoprotective compound N-acetylcysteine. Four days after cisplatin administration, AKI was induced in cisplatin-treated male Wistar rats (Cis group), as it was corroborated by increased urea and creatinine plasma levels. Tubular damage was also observed. In cotreated animals (Cis + NAC group), plasma urea and creatinine concentrations tended to return to their basal values, and tubular damage was improved. Urinary excretion of exosomal Oat5 was notably increased in the Cis group, but when renal injury was ameliorated by N-acetylcysteine coadministration, that increase was undetected. So, in this work we observed that urinary excretion of exosomal Oat5 was only increased if renal insult is produced, demonstrating its specificity as a renal injury biomarker.

Asunto(s)

Acetilcisteína/administración & dosificación , Biomarcadores/orina , Transportadores de Ácidos Dicarboxílicos/orina , Riñón/lesiones , Nefrosis/diagnóstico , Animales , Cisplatino/toxicidad , Electroforesis , Immunoblotting , Riñón/efectos de los fármacos , Masculino , Nefrosis/tratamiento farmacológico , Nefrosis/prevención & control , Transportadores de Anión Orgánico/orina , Ratas , Ratas Wistar