Consequences of bile duct obstruction on intestinal expression and function of multidrug resistance-associated protein 2.
OBJECTIVE
Multidrug resistance-associated protein 2 (MRP2), a transporter of organic anions in hepatocytes, renal epithelial cells, and enterocytes, is differentially regulated in liver and kidney during cholestasis, but little is known about its regulation in the intestine.


METHODS
We investigated duodenal protein expression of MRP2 in male Sprague-Dawley rats with bile duct ligation (BDL) or biliary diversion as well as in 20 cholestatic patients with biliary obstruction.


RESULTS
In biliary obstruction, but not biliary depletion, intestinal Mrp2 protein mass was reduced to 9.3% +/- 5.5% of controls and mRNA to 40.5% +/- 20.8% of controls after 7 days. Binding of RXR alpha:RAR alpha heterodimers to the Mrp2 promoter element was significantly reduced in BDL rats. Cytokine blockade identified IL-1 beta as the responsible inducer of Mrp2 down-regulation. In humans with obstructive cholestasis, intestinal MRP2 protein expression was reduced to 27.3% +/- 20.3% of control patients; this reduction correlated with the duration of cholestasis and was reversible after reconstitution of bile flow by stenting of the common bile duct. However, no significant differences in MRP2 mRNA levels were detected by RT-PCR in humans. Intestinal protein expression of P-glycoprotein, breast cancer resistance protein (BCRP), and MRP3 was unchanged. In BDL rats, oral bioavailability of the Mrp2 substrate and food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) was elevated 2.5 times compared with sham-operated rats.


CONCLUSIONS
Cholestasis promotes down-regulation of MRP2 expression in the duodenum of rats and humans. Selective down-regulation during cholestasis might be the consequence of species-specific transcriptional and posttranscriptional mechanisms and contributes to higher bioavailability of a food-derived carcinogen.
Dietrich
Christoph G
CG
Department of Internal Medicine III, Aachen University, Germany. cdietrich@ukaachen.dk
Geier
Andreas
A
Salein
Nina
N
Lammert
Frank
F
Roeb
Elke
E
Oude Elferink
Ronald P J
RP
Matern
Siegfried
S
Gartung
Carsten
C
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002250:Carbon Radioisotopes; D002273:Carcinogens / Q000493:pharmacokinetics; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002779:Cholestasis / Q000503:physiopathology* / Q000601:surgery; D004386:Duodenum / Q000502:physiology*; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics; D007375:Interleukin-1 / Q000037:antagonists & inhibitors; D008026:Ligation; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D002250:Carbon Radioisotopes; D002273:Carcinogens; D002352:Carrier Proteins; D007093:Imidazoles; D007375:Interleukin-1; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D014409:Tumor Necrosis Factor-alpha; C116614:ABCG2 protein, human; C423013:Abcc2 protein, rat; C114462:multidrug resistance-associated protein 3; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine