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1.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artículo en Inglés | MEDLINE | ID: mdl-34208557

RESUMEN

The organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1) mediate the renal secretion of drugs. Recent studies suggest that ondansetron, a 5-HT3 antagonist drug used to prevent nausea and vomiting, can inhibit OCT2- and MATE1-mediated transport. The purpose of this study was to test the ability of five 5-HT3 antagonist drugs to inhibit the OCT2 and MATE1 transporters. The transport of the OCT2/MATE1 probe substrate ASP+ was assessed using two models: (1) HEK293 kidney cells overexpressing human OCT2 or MATE1, and (2) MDCK cells transfected with human OCT2 and MATE1. In HEK293 cells, the inhibition of ASP+ uptake by OCT2 listed in order of potency was palonosetron (IC50: 2.6 µM) > ondansetron > granisetron > tropisetron > dolasetron (IC50: 85.4 µM) and the inhibition of ASP+ uptake by MATE1 in order of potency was ondansetron (IC50: 0.1 µM) > palonosetron = tropisetron > granisetron > dolasetron (IC50: 27.4 µM). Ondansetron (0.5-20 µM) inhibited the basolateral-to-apical transcellular transport of ASP+ up to 64%. Higher concentrations (10 and 20 µM) of palonosetron, tropisetron, and dolasetron similarly reduced the transcellular transport of ASP+. In double-transfected OCT2-MATE1 MDCK cells, ondansetron at concentrations of 0.5 and 2.5 µM caused significant intracellular accumulation of ASP+. Taken together, these data suggest that 5-HT3 antagonist drugs may inhibit the renal secretion of cationic drugs by interfering with OCT2 and/or MATE1 function.


Asunto(s)
Antieméticos/farmacología , Riñón/efectos de los fármacos , Riñón/metabolismo , Proteínas de Transporte de Catión Orgánico/biosíntesis , Transportador 2 de Cátion Orgánico/biosíntesis , Animales , Antieméticos/química , Transporte Biológico/efectos de los fármacos , Línea Celular , Células Cultivadas , Perros , Expresión Génica , Células HEK293 , Humanos , Células de Riñón Canino Madin Darby , Estructura Molecular , Proteínas de Transporte de Catión Orgánico/genética , Proteínas de Transporte de Catión Orgánico/metabolismo , Transportador 2 de Cátion Orgánico/genética , Antagonistas del Receptor de Serotonina 5-HT3/farmacología
2.
Am J Surg Pathol ; 45(1): 35-44, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33177341

RESUMEN

Rosai-Dorfman disease (RDD) is a rare histiocytosis with heterogenous clinical features. In this study, we characterized the histologic and phenotypic features in 33 RDD patients to better define the pathologic diagnosis. Cases included 24 patients with extracutaneous disease ("R" group), and 9 patients with lesions limited to the skin or subcutaneous tissue ("C" group). We identified OCT2 as a novel marker for the monocyte-macrophage phenotype of RDD, expressed in 97% of RDD cases. In contrast, OCT2 expression was seen in 0% of Erdheim-Chester disease cases and 6.7% of Langerhans cell histiocytosis cases. Other markers useful in the diagnosis of RDD included S100 (100%), CD163 (88%), and cyclin D1 (97%). In a subset of cases, RDD showed moderate to strong expression of factor 13a (30%), p16 (64%), and phosphorylated extracellular signal-regulated kinase (45%); RDD was uniformly negative for ZBTB46, CD1a, and langerin. Within the "R group" of RDD, increased expression of factor 13a or phosphorylated extracellular signal-regulated kinase showed a statistically significant association with multifocal disease (P<0.05). Identification of the unique monocyte-macrophage phenotype of RDD with OCT2 expression furthers our understanding of this complex disease and allows for more uniform classification.


Asunto(s)
Biomarcadores/análisis , Histiocitosis Sinusal/clasificación , Histiocitosis Sinusal/patología , Transportador 2 de Cátion Orgánico/biosíntesis , Adulto , Anciano , Femenino , Humanos , Macrófagos , Masculino , Persona de Mediana Edad , Monocitos , Transportador 2 de Cátion Orgánico/análisis , Adulto Joven
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