Atp-dependent transport of estradiol-17[beta]-([beta]-d
-glucuronide) in rat canalicular membrane vesicles.
Vore, Mary, Tim Hoffman, and Michael Gosland.
Department of Pharmacology, College of Medicine, (MV/TH), Graduate
Center for Toxicology (MV) and College of Pharmacy (MG), University
of Kentucky, Lexington, KY 40536
APStracts 3:0093G, 1996.
The ATP-dependent transport of estradiol-17[beta]([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 (Km, 75 [mu]M; Vmax, 598
pmol/min/mg protein). The steroid conjugates, estradiol-3
-glucuronide, estriol-3-glucuronide, estriol-16[alpha]-glucuronide,
testosterone glucuronide and the 3-sulfate conjugate of E217G were
effective inhibitors of transport. Bromosulfophthalein, S-(2,4
-dinitrophenyl)glutathione, glutathione disulfide, 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, E2 17G 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 a
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.
Received 8 June 1994; accepted in final form 21 April 1996.
APS Manuscript Number G220-4.
Article publication pending Am. J. Physiol. (Gastrointest. Liver
Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 8 May 96