Abstract:
BACKGROUND & AIMS:Drug-induced cholestasis is a frequent form of acquired liver disease. To elucidate the molecular pathogenesis of drug-induced cholestasis, we investigated the effects of prototypic cholestatic drugs on the canalicular bile salt export pump (Bsep) of rat liver. METHODS:Vesicles were isolated from Bsep-, Mrp2-, and Bsep/Mrp2-expressing Sf9 cells. Canalicular plasma membrane (cLPM) vesicles from rat liver and Sf9 cell vesicles were used to study adenosine triphosphate (ATP)-dependent solute uptake by a rapid filtration technique. RESULTS:Bsep-expressing Sf9 cell vesicles showed ATP-dependent transport of numerous monoanionic bile salts with similar Michaelis constant values as in cLPM vesicles, whereas several known substrates of the multispecific organic anion transporter Mrp2 were not transported by Bsep. Cyclosporin A, rifamycin SV, rifampicin, and glibenclamide cis-inhibited Bsep-mediated bile salt transport to similar extents as ATP-dependent taurocholate transport in cLPM vesicles. In contrast, the cholestatic estrogen metabolite estradiol-17beta-glucuronide inhibited ATP-dependent taurocholate transport only in normal cLPM and in Bsep/Mrp2-coexpressing Sf9 cell vesicles, but not in Mrp2-deficient cLPM or in selectively Bsep-expressing Sf9 cell vesicles, indicating that it trans-inhibits Bsep only after its secretion into bile canaliculi by Mrp2. CONCLUSIONS:These results provide a molecular basis for previous in vivo observations and identify Bsep as an important target for induction of drug- and estrogen-induced cholestasis in mammalian liver.
journal_name
Gastroenterologyjournal_title
Gastroenterologyauthors
Stieger B,Fattinger K,Madon J,Kullak-Ublick GA,Meier PJdoi
10.1016/s0016-5085(00)70224-1keywords:
subject
Has Abstractpub_date
2000-02-01 00:00:00pages
422-30issue
2eissn
0016-5085issn
1528-0012pii
S0016508500987523journal_volume
118pub_type
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