Ethinyl estradiol cholestasis involves alterations in expression of liver sinusoidal transporters

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

Research output: Contribution to journalArticle

120 Scopus citations

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)
Pages (from-to)G1043-G1052
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume271
Issue number6 34-6
DOIs
StatePublished - Jan 1 1996
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

Fingerprint Dive into the research topics of 'Ethinyl estradiol cholestasis involves alterations in expression of liver sinusoidal transporters'. Together they form a unique fingerprint.

  • Cite this