Cyclosporin A and a diaziridine derivative inhibit the hepatocellular uptake of cholate, phalloidin and rifampicin.
Cyclosporin A inhibits the uptake of cholate into isolated hepatocytes in a non-competitive manner (Ki = 3.6 microM). It protects liver cells against phalloidin injury by a mixed competitive/non-competitive inhibition of phalloidin uptake (Ki = 0.08 microM). Rifampicin, a well-known substrate of the bilirubin transporter is also incorporated in a decreased quantity in the presence of cyclosporin A (IC50 = 80 microM). A photolabile diaziridine derivative of cyclosporin A was used for the identification of binding sites. In comparison with the original cyclosporin A the photoaffinity label exhibits a 2-3-fold lower affinity to the cholate (and phalloidin) transporter in the liver cell membrane. In the dark the label inhibits the uptake of both cholate and of phalloidin reversibly; after treatment with ultraviolet light flashes the inhibition becomes irreversible. The degree of inhibition is concentration dependent. Our results suggest binding of cyclosporin A to protein components of the cholate (and phalloidin) transporter of liver cells without uptake by this system. The inhibition of cholate (and phalloidin) uptake by cyclosporin A is non-competitive and may be due to nonspecific hydrophobic binding to compounds of the cholate transporter.
D000621:Aminoisobutyric Acids / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D002286:Carcinoma, Ehrlich Tumor / Q000378:metabolism; D019826:Cholic Acid; D002793:Cholic Acids / Q000378:metabolism*; D003524:Cyclosporins / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D009842:Oligopeptides / Q000378:metabolism*; D010590:Phalloidine / Q000378:metabolism*; D012293:Rifampin / Q000378:metabolism*
D000621:Aminoisobutyric Acids; D002793:Cholic Acids; D003524:Cyclosporins; D009842:Oligopeptides; C048004:cyclosporin diaziridine; D010590:Phalloidine; C100049:2-aminoisobutyric acid; D019826:Cholic Acid; D012293:Rifampin