Effect of phenobarbital on the expression of bile salt and organic anion transporters of rat liver.
OBJECTIVE
The hepatic clearance of drugs and cholephilic organic anions is stimulated by phenobarbital (PB). Our aim was to analyze the effects of PB on the expression of hepatocellular bile salt and organic anion transporters.


METHODS
Male Sprague-Dawley rats were treated intraperitoneally with PB (80 mg/kg/d) or saline for 5 days. Transporter expression was quantified by northern and western blot analysis and initial uptake rates of bromosulphophthalein (BSP) and digoxin were measured in isolated hepatocytes.


RESULTS
Compared to control rats, PB treatment increased expression of the organic anion transporting polypeptide 2 (Oatp2; Slc21aS) more than 2-fold on the RNA (P < 0.05) and protein (P < 0.001) levels. Expression of Oatpl (Slc21al), Oatp4 (Slc21a6) and the Na+-taurocholate cotransporting polypeptide (Ntcp; Slc10a1) was unaltered. At the canalicular pole, expression of the bile salt export pump (Bsep; ABCB11) and of the multidrug resistance proteins 2 (Mrp2; ABCC2) and 6 (Mrp6; ABCC6) was not significantly changed. Whereas hepatocellular BSP uptake was unaffected by PB, digoxin uptake was stimulated 4-fold.


CONCLUSIONS
The induction of digoxin uptake by PB correlates with Oatp2 expression. In contrast, the lack of increase of Oatpl and Oatp4 expression is in accordance with unchanged BSP uptake. These data challenge the previously held view that PB induces hepatocellular BSP uptake systems.
Hagenbuch
N
N
Department of Medicine, University Hospital, Zurich, Switzerland.
Reichel
C
C
Stieger
B
B
Cattori
V
V
Fattinger
K E
KE
Landmann
L
L
Meier
P J
PJ
Kullak-Ublick
G A
GA
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001693:Biological Transport, Active / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D004077:Digoxin / Q000493:pharmacokinetics; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D027362:Organic Anion Transport Protein 1 / Q000235:genetics / Q000378:metabolism; D029363:Organic Anion Transporters, Sodium-Dependent; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013448:Sulfobromophthalein / Q000493:pharmacokinetics; D027981:Symporters
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D002352:Carrier Proteins; D004077:Digoxin; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027362:Organic Anion Transport Protein 1; D029363:Organic Anion Transporters, Sodium-Dependent; D029362:Organic Anion Transporters, Sodium-Independent; D010634:Phenobarbital; D012333:RNA, Messenger; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013448:Sulfobromophthalein; D027981:Symporters; C000715087:ABCC2 protein, human; C102029:ABCC6 protein, human; C490548:Abcb11 protein, rat; C490280:SLC22A7 protein, human; C088800:Slc22a7 protein, rat; C421207:Slco1b2 protein, rat; C071908:sodium-bile acid cotransporter; C421109:multidrug resistance-associated protein 1