Cyclosporin A and a diaziridine derivative inhibit the hepatocellular uptake of cholate, phalloidin and rifampicin

Biochim Biophys Acta. 1986 Feb 13;855(1):136-42. doi: 10.1016/0005-2736(86)90197-5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoisobutyric Acids / metabolism
  • Animals
  • Biological Transport
  • Carcinoma, Ehrlich Tumor / metabolism
  • Cholic Acid
  • Cholic Acids / metabolism*
  • Cyclosporins / pharmacology*
  • Kinetics
  • Liver / drug effects
  • Liver / metabolism*
  • Mice
  • Oligopeptides / metabolism*
  • Phalloidine / metabolism*
  • Rifampin / metabolism*


  • Aminoisobutyric Acids
  • Cholic Acids
  • Cyclosporins
  • Oligopeptides
  • cyclosporin diaziridine
  • Phalloidine
  • 2-aminoisobutyric acid
  • Cholic Acid
  • Rifampin