ATP-dependent transport of beta-estradiol 17-(beta-D-glucuronide) in rat canalicular membrane vesicles.
The ATP-dependent transport of beta-estradiol 17-(beta-D-glucuronide) (E217G), a cholestatic metabolite of estradiol, was investigated in rat liver canalicular membrane vesicles. ATP-dependent transport was dependent on time and temperature and occurred into an osmotically sensitive space; kinetic analysis indicated a saturable transport system (Michaelis-Menten constant value, 75 microM; maximum transport rate, 598 pmol.min-1.mg protein-1). The steroid conjugates estradiol glucuronide, estriol 3-glucuronide, estriol 16 alpha-glucuronide, testosterone glucuronide, and the three-sulfate conjugate of 17G were effective inhibitors of transport. Bromosulfophthalein, S-(2,4-dinitrophenyl)glutathione, and glutathione disulfide, all substrates of the canalicular ATP-dependent non-bile acid organic anion transport system, were also effective inhibitors, whereas taurocholate had no effect on transport. Conversely, E217G inhibited the ATP-dependent transport of S-(2,4-dinitrophenyl)glutathione. Daunorubicin, vinblastine, etoposide, cyclosporin, and PSC-833, substrates/modulators of P-glycoprotein, were also potent inhibitors of E217G transport, and E217G competitively inhibited the ATP-dependent transport of daunorubicin. C219, a monoclonal antibody against P-glycoprotein, inhibited ATP-dependent transport of E217G and daunorubicin but not of taurocholate or S-(2,4-dinitrophenyl)glutathione. These data indicate that E217G is substrate of both the non-bile acid organic anion transport system and P-glycoprotein but not of the ATP-dependent bile acid transport system in canalicular membranes.
Vore
M
M
Department of Pharmacology, College of Medicine, University of Kentucky, Lexington 40536, USA.
Hoffman
T
T
Gosland
M
M
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001648:Bile Canaliculi / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism; D005965:Glucuronates / Q000494:pharmacology; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012265:Ribonucleotides / Q000494:pharmacology
D000970:Antineoplastic Agents; D005965:Glucuronates; D012265:Ribonucleotides; C025483:estradiol-17 beta-glucuronide; C022571:adenosine 5'-O-(3-thiotriphosphate); D004958:Estradiol; D000255:Adenosine Triphosphate; D005978:Glutathione