Ethinyl estradiol cholestasis involves alterations in expression of liver sinusoidal transporters

Francis R. Simon, John Fortune, Mieko Iwahashi, Carsten Gartung, Allan W. Wolkoff, Eileen Sutherland

Research output: Contribution to journalArticle

119 Citations (Scopus)

Abstract

The mechanisms involved in ethinyl estradiol-induced cholestasis are controversial. Basal bile flow was reduced by ethinyl estradiol administration, with a half time (t( 1/4 )) 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 t( 1/4 ) 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 α-subunit nor β-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 t( 1/4 ) 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 ~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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume271
Issue number6 34-6
StatePublished - 1996
Externally publishedYes

Fingerprint

Ethinyl Estradiol
Cholestasis
Taurocholic Acid
Organic Anion Transporters
Liver
Membrane Fluidity
Adenosine Triphosphatases
Membrane Lipids
Messenger RNA
Proteins
Bile Acids and Salts
Bile
Carrier Proteins
Membranes

Keywords

  • bile acids
  • fluidity
  • organic anion transporter
  • sodium-dependent bile acid transporter
  • sodium-potassium-activated adenosinetriphosphatase

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology

Cite this

Ethinyl estradiol cholestasis involves alterations in expression of liver sinusoidal transporters. / Simon, Francis R.; Fortune, John; Iwahashi, Mieko; Gartung, Carsten; Wolkoff, Allan W.; Sutherland, Eileen.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 271, No. 6 34-6, 1996.

Research output: Contribution to journalArticle

Simon, Francis R. ; Fortune, John ; Iwahashi, Mieko ; Gartung, Carsten ; Wolkoff, Allan W. ; Sutherland, Eileen. / Ethinyl estradiol cholestasis involves alterations in expression of liver sinusoidal transporters. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 1996 ; Vol. 271, No. 6 34-6.
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