RESUMEN
Organic anion transporters (OATs) and organic cation transporters (OCT) play pivotal roles in the uptake of drugs into epithelial cells at the basolateral membranes, and multidrug and toxin extrusion (MATE) mediates drug secretion into urine at the brush-border membranes. In this study, the expression and distribution of apical MATE1 and MATE2-K, and basolateral OAT1, OAT3, and OCT2 were compared using serial sections of human kidney cortex. First, mRNA expression in the proximal tubules was evaluated using laser microdissection. Levels of OAT, OCT2, and MATE mRNA in the proximal tubules were greatly higher compared with glomerulus. The results quantitatively indicated that these transporters were localized to proximal tubules in the renal cortex. Second, MATE1 and MATE2-K protein were detected in proximal epithelial cells in which OCT2 protein was expressed at the basolateral membranes. In addition, MATE1 was expressed at the brush-border membranes of tubular epithelial cells in which OAT1 and OAT3 were expressed. The results confirmed that OAT1, OAT3, OCT2, MATE1, and MATE2-K were coexpressed in tubular epithelial cells. The cooperation among OAT, OCT, and MATE in renal drug secretion was consistent with their distribution.
Asunto(s)
Riñón/metabolismo , Proteína 1 de Transporte de Anión Orgánico/análisis , Transportadores de Anión Orgánico Sodio-Independiente/análisis , Proteínas de Transporte de Catión Orgánico/análisis , Anciano , Expresión Génica , Humanos , Inmunohistoquímica , Riñón/ultraestructura , Masculino , Persona de Mediana Edad , Proteína 1 de Transporte de Anión Orgánico/genética , Transportadores de Anión Orgánico Sodio-Independiente/genética , Proteínas de Transporte de Catión Orgánico/genética , Transportador 2 de Cátion Orgánico , ARN Mensajero/análisis , ARN Mensajero/genéticaRESUMEN
The (2R,5S)-trans- and (2S,5S)-cis-stereoisomers 1a and 1b of 4(5)-(5-aminotetrahydropyran-2-yl)imidazole, which have two chiral centers and adopt a stable chair conformation, were synthesized via cyclization of diol intermediates 7 using L-glutamine as the starting material. Their enantiomers, (2S,5R)-trans-1c and (2R,5R)-cis-1d, were synthesized by the same methodology from D-glutamine. Stereo isomers 1a-d were converted into cyanoguanidines 11a-d, and into N-isopropyl and N-3,3-dimethylbutyl derivatives 12a-d and 13a-d, respectively. The results of in vivo brain microdialysis of the derivatives apparently indicated that only (2S,5R)-isomers increased the release of neuronal histamine. Among the many (2S,5R)-N-alkyl derivatives, 13c (OUP-133) and 18 (OUP-153) increased histamine release to 180-190% and 180-200% of basal levels, respectively, and were found to be novel histamine H(3) antagonists.
