Effect of Ursodeoxycholic Acid on the Expression of the Hepatocellular Bile Acid Transporters (Ntcp and bsep) in Rats With Estrogen-Induced Cholestasis.
OBJECTIVE
Rats with ethinyl estradiol-induced cholestasis have a decreased bile flow and a decreased expression of basolateral and canalicular hepatocyte membrane transporters. The bile acid ursodeoxycholic acid improves bile flow in these animals. The purpose of this study was to examine the effect of ursodeoxycholic acid on the expression of hepatocellular bile acid carriers.


METHODS
Rats received either ethinyl estradiol (5 mg.kg body wt. for 10 days) or ethinyl estradiol associated with ursodeoxycholic acid (1% in the diet). A third group of rats received ursodeoxycholic acid alone. Bile flow, bile acid, and glutathione biliary outputs were measured. Messenger RNA levels and protein expression of Na -dependent taurocholate co-transporting polypeptide, and bile salt export pump were determined in basolateral and canalicular membrane preparations by Northern and Western blot analysis.


RESULTS
Ursodeoxycholic acid restored bile flow in ethinyl estradiol-treated rats by increasing bile acid secretion. It did not improve glutathione output nor bile acid-independent flow. Na -dependent taurocholate co-transporting polypeptide mRNA and protein were decreased by ethinyl estradiol and not restored by ursodeoxycholic acid. In contrast, canalicular bile salt export pump protein expression was decreased by ethinyl estradiol and fully restored to control levels by ursodeoxycholic acid.


CONCLUSIONS
Ursodeoxycholic acid increases bile flow in ethinyl estradiol-treated rats by increasing bile acid secretion. This increase is possibly mediated by a normalization of the expression of the canalicular bile salt export pump.
Micheline
Dumont
D
Unité de Recherche des Mécanismes et Traitement des Meladies du Goie (Inserm U 481), Hôpital Beaujon, Clichy, France. dumont@bichat.inserm.fr
Emmanuel
Jacquemin
J
Serge
Erlinger
E
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D001693:Biological Transport, Active; D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D002779:Cholestasis / Q000139:chemically induced / Q000378:metabolism*; D045166:Estradiol Congeners / Q000633:toxicity; D004997:Ethinyl Estradiol / Q000494:pharmacology / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism; D006913:Hydroxysteroid Dehydrogenases; D015151:Immunoblotting; D008297:Male; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D027981:Symporters; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D002352:Carrier Proteins; D045166:Estradiol Congeners; D004997:Ethinyl Estradiol; D005978:Glutathione; D006913:Hydroxysteroid Dehydrogenases; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D012333:RNA, Messenger; D027981:Symporters; D014580:Ursodeoxycholic Acid; C490548:Abcb11 protein, rat; C037643:bile acid binding proteins; C071908:sodium-bile acid cotransporter; C435496:AKR1C2 protein, human; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)