Inhibition by cyclosporin A of adenosine triphosphate-dependent transport from the hepatocyte into bile.
BACKGROUND
Immunosuppressive treatment with cyclosporin A may be associated with impaired hepatobiliary elimination of bile salts and with cholestasis. Inhibition by cyclosporin A of the primary-active adenosine triphosphate (ATP)-dependent transport systems responsible for excretion of bile salts and cysteinyl leukotrienes across the hepatocyte canalicular membrane into bile may explain the cholestatic side effect.


METHODS
ATP-dependent transport of bile salt and of cysteinyl leukotrienes was studied in human liver plasma membrane vesicles and additionally in rat liver plasma membrane vesicles enriched in canalicular membranes.


RESULTS
Inhibition of ATP-dependent taurocholate transport in human liver by 50% was measured at 3 mumol/L cyclosporin A and at 4 mumol/L fujimycin. Kinetic analyses in rat liver indicated non-competitive inhibition by cyclosporin A with respect to ATP and competitive inhibition with respect to taurocholate with inhibition constant (Ki) values of 1.0 and 0.3 mumol/L, respectively.


CONCLUSIONS
The ATP-dependent export carriers for bile salts and cysteinyl leukotrienes in the hepatocyte canalicular membrane are novel targets for inhibitory side effects of cyclosporin A. Inhibition of ATP-dependent bile salt transport may induce cholestasis.
Kadmon
M
M
Division of Tumor Biochemistry, Deutsches Krebsforschungzentrum, Heidelberg, Germany.
Klünemann
C
C
Böhme
M
M
Ishikawa
T
T
Gorgas
K
K
Otto
G
G
Herfarth
C
C
Keppler
D
D
D000255:Adenosine Triphosphate / Q000502:physiology*; D000328:Adult; D001646:Bile / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D016572:Cyclosporine / Q000494:pharmacology*; D006801:Humans; D015289:Leukotrienes / Q000493:pharmacokinetics; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008875:Middle Aged; D013189:SRS-A / Q000494:pharmacology; D016559:Tacrolimus / Q000494:pharmacology; D013656:Taurocholic Acid / Q000493:pharmacokinetics
D015289:Leukotrienes; D013189:SRS-A; D013656:Taurocholic Acid; D016572:Cyclosporine; D000255:Adenosine Triphosphate; D016559:Tacrolimus