Moseley R H, Van Dyke R W
Department of Internal Medicine, Veterans Affairs Medical Center, Ann Arbor, Michigan.
Am J Physiol. 1995 Mar;268(3 Pt 1):G480-6. doi: 10.1152/ajpgi.1995.268.3.G480.
Hepatic organic cation transport has been characterized in rat liver plasma membrane vesicles, using the quaternary amine tetraethylammonium (TEA) as a model substrate. Sinusoidal TEA uptake is stimulated by an inside-negative membrane potential; TEA transport across the canalicular membrane is mediated by electroneutral organic cation-H+ exchange. Substrates for these transport processes include procainamide ethobromide (PAEB) and vecuronium, cationic drugs that undergo biliary excretion. Given the apparent absence of sinusoidal transport mechanisms able to generate high hepatocyte-to-blood organic cation concentration ratios, intracellular transport of organic cations may involve sequestration and concentration within acidified organelles. Therefore, the characteristics of TEA uptake were examined in isolated rat liver lysosomes that are acidified by a well-described H(+)-adenosinetriphosphatase (ATPase). Lysosomal uptake of [14C]TEA was a time- and ATP-dependent process, reaching steady state after 30-60 min. Steady-state [14C]TEA uptake was significantly reduced by omission of ATP and by addition of monensin, conditions that alter lysosomal pH and membrane potential gradients, and by the H(+)-ATPase inhibitors, N-ethylmaleimide and bafilomycin A. ATP-dependent lysosomal [14C]TEA uptake was significantly inhibited by PAEB, vecuronium, and other organic cationic substrates of canalicular TEA/H+ exchange. These findings demonstrate that rat liver lysosomes sequester certain organic cationic drugs, most likely via organic cation/H+ exchange driven by H(+)-ATPase. Canalicular organic cation/H+ exchange may reflect, in part, the exocytic insertion of this transporter from an intracellular compartment to this membrane domain.
肝有机阳离子转运已在大鼠肝细胞膜囊泡中得到表征，使用季铵盐四乙铵（TEA）作为模型底物。肝血窦侧的TEA摄取受膜内负电位刺激；TEA通过胆小管膜的转运由电中性有机阳离子-H⁺交换介导。这些转运过程的底物包括普鲁卡因胺乙溴化物（PAEB）和维库溴铵，这些阳离子药物会经胆汁排泄。鉴于明显不存在能够产生高肝细胞与血液有机阳离子浓度比的肝血窦侧转运机制，有机阳离子的细胞内转运可能涉及在酸化细胞器内的隔离和浓缩。因此，在由一种已充分描述的H⁺-腺苷三磷酸酶（ATP酶）酸化的分离大鼠肝溶酶体中研究了TEA摄取的特征。[¹⁴C]TEA的溶酶体摄取是一个时间和ATP依赖性过程，在30 - 60分钟后达到稳态。ATP缺失、添加莫能菌素（可改变溶酶体pH和膜电位梯度）以及添加H⁺-ATP酶抑制剂N-乙基马来酰亚胺和巴弗洛霉素A后，稳态[¹⁴C]TEA摄取显著降低。PAEB、维库溴铵和胆小管TEA/H⁺交换的其他有机阳离子底物显著抑制了ATP依赖性溶酶体[¹⁴C]TEA摄取。这些发现表明，大鼠肝溶酶体隔离某些有机阳离子药物，很可能是通过由H⁺-ATP酶驱动的有机阳离子/H⁺交换。胆小管有机阳离子/H⁺交换可能部分反映了该转运体从细胞内区室向该膜结构域的胞吐插入。
