Molecular diversity of organic ion transporters and their roles in the renal drug excretion

点击翻译按钮获取中文摘要

We have studied the structure, function and tubular localization of organic ion transporters expressed in the kidney to systematically elucidate the mechanisms of renal excretion process of ionic drugs.1. Organic cation transporter family : We demonstrated that OCT1 and OCT2 organic cation transporters recognized a variety of cationic drugs with similar substrate affinity. Immunocytochemical studies revealed that OCT1 and OCT2 were localized at the basolateral membrane of different tubular segments in the kidney. In addition, we found that the expression of OCT2, but not OCT1 and OCT3, was higher in the male kidney than the female kidney, and that the gender difference in OCT2 expression was regulated by sex hormones.2. Organic anion transporter family : We have characterized the substrate specificity of organic anion transporters, OAT1 and OAT-K1, using various heterologous expression systems. OAT1 recognized relatively hydrophilic organic anions, while OAT-K1 transports hydrophobic organic anions. We demonstrated that OAT1-mediated transport of methotrexate was competitively inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin and salicylate, suggesting that OAT1 is the major site of the transporter-mediated interaction between methotrexate and NSAIDs. In addition, we succeeded in cloning of a new organic anion transporter, OAT-K2. Functional analysis indicated that OAT-K2 also recognized a variety of hydrophobic organic anions like OAT-K1.These observations will help us to evaluate and predict the renal drug excretion. In addition, estimation of substrate affinity for each transporter could be useful to predict transporter-mediated drug interactions.