Ethinyl estradiol cholestasis involves alterations in expression of liver sinusoidal transporters.
The mechanisms involved in ethinyl estradiol-induced cholestasis are controversial. Basal bile flow was reduced by ethinyl estradiol administration, with a half time (t1/2) of 12.5 +/- 0.6 h. In contrast, initial taurocholate uptake was not significantly reduced until 3 days to 59% of control and to 13 and 10% of control at 5 and 7 days, respectively. The t1/2 was 4.3 +/- 0.1 days. These physiological changes were correlated with measurement of protein mass and steady-state mRNA for Na(+)-K(+)-adenosinetriphosphatase (Na(+)-K(+)-ATPase), Na(+)-dependent taurocholate transporter, organic anion transporters, and membrane lipid fluidity. Ethinyl estradiol significantly decreased Na(+)-K(+)-ATPase activity and membrane fluidity. However, neither Na(+)-K(+)-ATPase alpha-subunit nor beta-subunit mass was altered by ethinyl estradiol administration. In contrast, protein content of the Na(+)-dependent taurocholate transporter was significantly reduced to 21% of control (P < 0.001) at 5 days. The Na(+)-dependent taurocholate transporter was identified in sinusoidal membrane fractions as a doublet with a molecular size estimated to be 51 and 56 kDa. Although both bands were reduced with ethinyl estradiol treatment, the 56-kDa band was decreased more rapidly and to a greater extent than the 51-kDa band. The estimated t1/2 of 4.8 +/- 0.6 days for the doublet was similar to that for Na(+)-dependent taurocholate uptake. The organic anion transporter protein mass was similarly reduced with time of ethinyl estradiol administration to 21% of control (P < 0.01) at 5 days. Ethinyl estradiol also rapidly decreased the steady-state mRNA levels of Na(+)-dependent and organic anion transporters to approximately 50% and 15% of control at 5 days, respectively. These studies indicate early generalized abnormalities of the sinusoidal membrane lipid fluidity, Na(+)-K(+)-ATPase activity, and bile acid transport protein content.
Simon
F R
FR
Hepatobiliary Center, University of Colorado Health Sciences Center, Denver 80262, USA.
Fortune
J
J
Iwahashi
M
M
Gartung
C
C
Wolkoff
A
A
Sutherland
E
E
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects; D002779:Cholestasis / Q000139:chemically induced / Q000378:metabolism*; D004997:Ethinyl Estradiol / Q000008:administration & dosage*; D008099:Liver / Q000378:metabolism / Q000503:physiopathology* / Q000648:ultrastructure; D008297:Male; D008560:Membrane Fluidity / Q000187:drug effects; D029363:Organic Anion Transporters, Sodium-Dependent; D051381:Rats; D017207:Rats, Sprague-Dawley; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D027981:Symporters
D002352:Carrier Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; C071908:sodium-bile acid cotransporter; D004997:Ethinyl Estradiol; D000254:Sodium-Potassium-Exchanging ATPase