Hepatocellular uptake of peptides--II. Interactions between hydrophilic linear renin-inhibiting peptides and transport systems for endogenous substrates in liver cells.
To define the endogenous transport system responsible for the hepatocellular uptake of hydrophilic linear peptides, interactions between the cationic renin-inhibitor, [5(4-amino-piperidyl-1-carbonyl-L-2,6[3H]phenyl-alanyl-beta-alanyl(4S- amino-3S-hydroxy-5-cyclo-hexyl)-pentan-carbonyl-L-isoleucyl-ami nom ethyl-4-amino-2-methyl-pyrimidine-citrat] (code number EMD 56133; EMD, E. Merck, Darmstadt) and substrates of endogenous transport systems of liver cells were studied in isolated rat hepatocytes. EMD 56133 competitively inhibited the uptake of ouabain (Ki = 75 microM) and vice versa (Ki = 200 microM). In contrast, the sodium-dependent as well as the sodium-independent uptake of cholate and the total uptake of taurocholate were non-competitively blocked, whereas EMD 56133 decreased the uptake of the cyclosomatostatin 008 in an uncompetitive manner. EMD 56133 did not interfere with transport systems for monovalent organic cations, amino acids and long chain fatty acids. The uptake of rifampicin, however, was increased in the presence of EMD 56133. The transport of EMD 56133 was non-competitively inhibited by cholate (Ki = 126 microM) and taurocholate (Ki = 44 microM), and uncompetitively inhibited by the linear peptide EMD 51921. In contrast, the uncharged compound ouabain (Ki = 200 microM) and the bivalent organic cation d-tubocurarine (Ki = 370 microM) competitively inhibited the uptake of the renin inhibitor. Several substrates of other endogenous transport systems (e.g. bilirubin, cyclopeptides, monovalent cations, dipeptides, amino acids, fatty acids, hexoses) did not interfere with the transport of EMD 56133. Our results suggest that transport systems for bivalent organic cations or uncharged compounds (ouabain) are able to eliminate the linear hydrophilic peptide tested.
Seeberger
A
A
Institut für Pharmakologie und Toxikologie, Justus-Liebig Universität Giessen, Federal Republic of Germany.
Ziegler
K
K
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism; D002470:Cell Survival; D019826:Cholic Acid; D002793:Cholic Acids / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D019301:Oleic Acid; D009829:Oleic Acids / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D010042:Ouabain / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012694:Serine / Q000378:metabolism; D013656:Taurocholic Acid / Q000378:metabolism; D013831:Thiamine / Q000378:metabolism; D014403:Tubocurarine / Q000378:metabolism; D000092502:Renin Inhibitors
D001647:Bile Acids and Salts; D002352:Carrier Proteins; D019826:Cholic Acid; D002793:Cholic Acids; D019301:Oleic Acid; D009829:Oleic Acids; D009842:Oligopeptides; D010042:Ouabain; D010455:Peptides; D012694:Serine; D013656:Taurocholic Acid; D013831:Thiamine; D014403:Tubocurarine; D000092502:Renin Inhibitors; C080277:EMD 56133