Inhibition of bile acid transport by cyclosporine A in rat liver plasma membrane vesicles.
In selectively isolated basolateral (bILPM) and canalicular (cLPM) rat liver plasma membrane vesicles, the in vitro effect of cyclosporine A (CsA) on specific hepatic membrane transport processes was examined. CsA (0.1-200 microM) caused a concentration-dependent inhibition of initial rates of Na(+)-dependent taurocholate uptake in bILPM and cLPM vesicles and Na(+)-independent taurocholate efflux from cLPM vesicles. In contrast, CsA had no effect on Na(+)-dependent L-alanine uptake in bILPM and in cLPM vesicles. In addition, electroneutral pH gradient-driven Na+ uptake in bILPM vesicles was unaffected by CsA treatment. CsA-induced inhibition of taurocholate transport in bILPM and cLPM vesicles was competitive in nature. A hydroxylated (OL-17) and a N-demethylated (OL-21) metabolite of CsA had no effect on taurocholate transport in either membrane vesicle population. These findings suggest that the mechanism of CsA-induced cholestasis is, in part, the result of selective inhibition of bile acid transport by the parent compound at both domains of the hepatocyte plasma membrane.
Moseley
R H
RH
Department of Internal Medicine, Veterans Administration Medical Center, University of Michigan School of Medicine, Ann Arbor.
Johnson
T R
TR
Morrissette
J M
JM
D000409:Alanine / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D003524:Cyclosporins / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013656:Taurocholic Acid / Q000493:pharmacokinetics*
D003524:Cyclosporins; D013656:Taurocholic Acid; D000409:Alanine