Ethinyl estradiol cholestasis involves alterations in expression of liver sinusoidal transporters

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

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Abstract

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 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 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 -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. sodium-potassium-activated adenosinetriphosphatase; sodium-dependent bile acid transporter;.

Original languageEnglish (US)
Pages (from-to)G1039-G1042
JournalAmerican Journal of Physiology
Volume271
Issue number6 PART 1
Publication statusPublished - Dec 1 1996
Externally publishedYes

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Keywords

  • Bile acids
  • Fluidity
  • Organic anion transporter

ASJC Scopus subject areas

  • Physiology (medical)

Cite this

Simon, F. R., Fortune, J., Iwahashi, M., Gartung, G., Wolkoff, A., & Sutherland, E. (1996). Ethinyl estradiol cholestasis involves alterations in expression of liver sinusoidal transporters. American Journal of Physiology, 271(6 PART 1), G1039-G1042.