Dietrich Christoph G, Geier Andreas, Salein Nina, Lammert Frank, Roeb Elke, Oude Elferink Ronald P J, Matern Siegfried, Gartung Carsten
Department of Internal Medicine III, Aachen University, Germany.
Gastroenterology. 2004 Apr;126(4):1044-53. doi: 10.1053/j.gastro.2003.12.046.
BACKGROUND & AIMS: 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.
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.
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.
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.
多药耐药相关蛋白2（MRP2）是肝细胞、肾上皮细胞和肠上皮细胞中有机阴离子的转运体，在胆汁淤积期间肝脏和肾脏中其受到不同的调节，但关于其在肠道中的调节知之甚少。
我们研究了胆管结扎（BDL）或胆汁转流的雄性Sprague-Dawley大鼠以及20例胆道梗阻性胆汁淤积患者十二指肠中MRP2的蛋白表达。
在胆道梗阻而非胆汁耗竭时，7天后肠道Mrp2蛋白量降至对照组的9.3%±5.5%，mRNA降至对照组的40.5%±20.8%。BDL大鼠中RXRα:RARα异二聚体与Mrp2启动子元件的结合显著减少。细胞因子阻断确定IL-1β是Mrp2下调的诱导因子。在梗阻性胆汁淤积患者中，肠道MRP2蛋白表达降至对照患者的27.3%±20.3%；这种降低与胆汁淤积持续时间相关，并且在通过胆总管支架置入恢复胆汁流动后是可逆的。然而，通过RT-PCR在人类中未检测到MRP2 mRNA水平的显著差异。P-糖蛋白、乳腺癌耐药蛋白（BCRP）和MRP3的肠道蛋白表达未改变。在BDL大鼠中，Mrp2底物及食物源性致癌物2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶（PhIP）的口服生物利用度比假手术大鼠提高了2.5倍。
胆汁淤积促进大鼠和人类十二指肠中MRP2表达的下调。胆汁淤积期间的选择性下调可能是物种特异性转录和转录后机制的结果，并导致食物源性致癌物的生物利用度更高。
