Carrier-mediated hepatic uptake of peptidic endothelin antagonists in rats
| Autor: | Akhteruzzaman S, Kato Y, Kouzuki H, Suzuki H, Hisaka A, Stieger B, Pj, Meier, Sugiyama Y |
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| Rok vydání: | 1999 |
| Předmět: |
Endothelin Receptor Antagonists
Male Hydrocarbons Fluorinated Biological Transport Active Azepines Transfection Binding Competitive Peptides Cyclic Rats Rats Sprague-Dawley Kinetics Liver Anesthetics Inhalation COS Cells Animals Carrier Proteins Peptides Oligopeptides Antihypertensive Agents Cells Cultured Ethers |
| Zdroj: | Europe PubMed Central |
| ISSN: | 0022-3565 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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