Inhibition of taurocholate and ouabain transport in isolated rat hepatocytes by cyclosporin A.
The use of cyclosporin A in transplantation procedures has been reported to cause hepatotoxicity as evidenced by elevated serum bilirubin and bile salt levels. However, these biochemical abnormalities could also result from interference with hepatic transport processes. This possibility was investigated in the present study in which the effect of cyclosporin A on transport processes was examined in isolated rat liver cells. Taurocholate, ouabain, and alpha-aminoisobutyric acid were selected as compounds known to enter liver cells by distinct active transport systems and cadmium was selected as a substance taken up by a combination of simple and facilitated diffusion. Cyclosporin A was found to cause a dose-related inhibition of both taurocholate and ouabain uptake. On the other hand, the uptake of alpha-aminoisobutyric acid and of cadmium were unaffected by cyclosporin A. These findings indicate a substrate-specific effect of cyclosporin A rather than a general effect on cellular transport. Efflux of taurocholate from preloaded hepatocytes was also inhibited by cyclosporin A. Cyclosporin A caused a decrease in maximum velocity for ouabain uptake with no change in Km. Kinetic analysis for both uptake and efflux of taurocholate showed an unchanged maximum velocity and an increased Km. The data indicate that the ability of liver cells to take up and release bile acids is impaired in the presence of cyclosporin A. These findings provide a possible explanation for the finding of increased serum bile acids during cyclosporin A therapy and suggest that hepatic clearance of other compounds could also be impaired.
Stacey
N H
NH
National Occupational Health and Safety Commission, University of Sydney, Australia.
Kotecka
B
B
D000621:Aminoisobutyric Acids / Q000493:pharmacokinetics; D000818:Animals; D001692:Biological Transport; D002104:Cadmium / Q000493:pharmacokinetics; D003524:Cyclosporins / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D010042:Ouabain / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D013656:Taurocholic Acid / Q000493:pharmacokinetics*
D000621:Aminoisobutyric Acids; D003524:Cyclosporins; D002104:Cadmium; D010042:Ouabain; D013656:Taurocholic Acid