Akhteruzzaman S, Kato Y, Kouzuki H, Suzuki H, Hisaka A, Stieger B, Meier P J, Sugiyama Y
Graduate School of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan.
J Pharmacol Exp Ther. 1999 Sep;290(3):1107-15.
The endothelin antagonist BQ-123, an anionic cyclopentapeptide, is taken up by rat hepatocytes through active transport systems. Here, we have examined the hepatocellular uptake mechanism for several BQ-123 derivatives with anionic charges using isolated rat hepatocytes. BQ-485, a linear peptide, BQ-518, a cyclic peptide, and compound A, a cyclic peptide with a cationic moiety, were taken up by hepatocytes in a concentration-dependent manner. The uptake of BQ-485 was most efficient, whereas compound A showed comparable uptake with BQ-123. The uptake of these peptides was Na(+)- and energy-dependent, suggesting that active transport mechanisms are involved in their uptake into hepatocytes. BQ-485, BQ-518, and compound A can almost completely inhibit both the Na(+)-dependent and -independent uptake of [(3)H]BQ-123, with inhibition constants (K(i)) that are comparable to the Michaelis-Menten constants (K(m)) for their Na(+)-dependent and -independent uptake, respectively. Inhibition by BQ-485 was competitive, and the uptake of BQ-485 can be inhibited by BQ-123, with K(i) values that are comparable with the K(m) values for BQ-123 uptake. The uptake of BQ-123 by COS-7 cells transfected with either Na(+)-dependent taurocholate-cotransporting polypeptide (Ntcp) or Na(+)-independent basolateral organic anion-transporting polypeptide (oatp1) was minimal. Thus, these three peptides share the transporters that also recognize BQ-123 but appear to differ from Ntcp and oatp1.
内皮素拮抗剂BQ - 123是一种阴离子环五肽，通过主动转运系统被大鼠肝细胞摄取。在此，我们使用分离的大鼠肝细胞研究了几种带阴离子电荷的BQ - 123衍生物的肝细胞摄取机制。线性肽BQ - 485、环肽BQ - 518和带有阳离子部分的环肽化合物A以浓度依赖的方式被肝细胞摄取。BQ - 485的摄取效率最高，而化合物A的摄取与BQ - 123相当。这些肽的摄取依赖于Na⁺且需要能量，表明主动转运机制参与了它们进入肝细胞的过程。BQ - 485、BQ - 518和化合物A几乎可以完全抑制[(³)H]BQ - 123的Na⁺依赖性和非Na⁺依赖性摄取，其抑制常数（K(i)）分别与它们的Na⁺依赖性和非Na⁺依赖性摄取的米氏常数（K(m)）相当。BQ - 485的抑制作用具有竞争性，并且BQ - 123可以抑制BQ - 485的摄取，其K(i)值与BQ - 123摄取的K(m)值相当。用Na⁺依赖性牛磺胆酸盐共转运多肽（Ntcp）或非Na⁺依赖性基底外侧有机阴离子转运多肽（oatp1）转染的COS - 7细胞对BQ - 123的摄取极少。因此，这三种肽共享也能识别BQ - 123的转运体，但似乎与Ntcp和oatp1不同。
