Steen H, Oosting R, Meijer D K
Department of Pharmacology and Therapeutics, University of Groningen, The Netherlands.
J Pharmacol Exp Ther. 1991 Aug;258(2):537-43.
The mechanisms of hepatic organic cation transport were examined in isolated rat hepatocytes, using the model compound [methyl-3H]tributylmethylammonium (TBuMA). [3H]TBuMA is shown to be taken up into rat hepatocytes by two carrier-mediated systems in addition to a nonsaturable process. The transport mechanisms for TBuMA share common features with both the type I and type II carrier systems reported for exogenous organic cations such as procainamide ethobromide and vecuronium, respectively. Only slight effects were seen in the presence of relatively high concentrations of endogenous organic cations such as thiamine, choline and N1-methyl nicotinamide. The total uptake of [3H]TBuMA was neither influenced by an electronegative membrane potential and variations in external and internal pH, nor by the absence of Na+, K+ or Cl- in the incubation medium. The presence of the inorganic anion I- stimulated the uptake of [3H]TBuMA. An improved presentation or binding to the carrier may be involved because symport with the anion could not be demonstrated. Lowering of the temperature produced a significant reduction in the uptake velocity of [3H] TBuMA, whereas metabolic inhibitors such as valinomycin and carbonylcyanide-m-chlorphenylhydrazone reduced the uptake rate by 80 and 90%, respectively, which was correlated with the extent of ATP depletion. It is concluded that the monovalent cationic drug TBuMA can be considered as a mixed type I/type II compound that exhibits an electroneutral and anion-sensitive uptake mechanism, depending on metabolic energy. The uptake mechanism is dissimilar from Na(+)-dependent and H(+)-dependent transport systems that have been described for endogenous cations, such as thiamine, choline and N1-methylnicotinamide.
利用模型化合物[甲基-³H]三丁基甲基铵（TBuMA），在分离的大鼠肝细胞中研究了肝脏有机阳离子转运机制。除了非饱和过程外，[³H]TBuMA通过两种载体介导系统被摄取到大鼠肝细胞中。TBuMA的转运机制与分别报道的外源性有机阳离子如普鲁卡因胺、依托溴铵和维库溴铵的I型和II型载体系统具有共同特征。在存在相对高浓度的内源性有机阳离子如硫胺素、胆碱和N1-甲基烟酰胺时，仅观察到轻微影响。[³H]TBuMA的总摄取既不受负膜电位以及细胞外和细胞内pH变化的影响，也不受孵育培养基中不存在Na⁺、K⁺或Cl⁻的影响。无机阴离子I⁻的存在刺激了[³H]TBuMA的摄取。可能涉及到与载体更好的结合或呈现，因为未证明与阴离子的协同转运。降低温度会使[³H]TBuMA的摄取速度显著降低，而代谢抑制剂如缬氨霉素和羰基氰化物间氯苯腙分别使摄取率降低80%和90%，这与ATP耗竭程度相关。结论是单价阳离子药物TBuMA可被视为一种I型/II型混合型化合物，其表现出一种电中性且对阴离子敏感的摄取机制，这取决于代谢能量。该摄取机制与已描述的内源性阳离子如硫胺素、胆碱和N1-甲基烟酰胺的Na⁺依赖性和H⁺依赖性转运系统不同。
