Disease relevance of Abcb4

• We investigated the role of Mrp2 in phalloidin-induced cholestasis [1].
• Gene expression of the canalicular conjugate transporter mrp2 is inducible by treatment with the DNA-damaging agents 2-acetylaminofluorene (50 and 100 microM), and cisplatin (20 microM) in primary rat hepatocytes as well as in the rat hepatoma cell line H4IIE [2].

High impact information on Abcb4

• RESULTS: In diabetic rats, hepatic gene and protein expression of the multidrug resistance P-glycoprotein type 2 (Mdr2) were increased by 105% and 530%, respectively, associated with increased biliary phospholipid output (+520%) and phospholipid/bile salt ratio (+77%) [3].
• Mdr2((-/-)) mice do not secrete phospholipids and cholesterol into bile, and bile salt secretion is not impaired [4].
• BACKGROUND & AIMS: Endotoxin lipopolysaccharide (LPS) induces cholestasis and down-regulates the multidrug resistance protein 2 (MRP2) [5].
• Dexamethasone counteracted the LPS effects on MRP2 mRNA levels, subcellular distribution, and BSP excretion [5].
• CONCLUSIONS: LPS induces cholestasis due to an early retrieval of MRP2 from the canalicular membrane, whereas down-regulation of MRP2 mRNA is a later event [5].

Chemical compound and disease context of Abcb4

• (3) Polymyxin B, but not the other antibiotics, prevented alterations in immunostaining for both 7H6 and mrp2, and cholestasis [6].
• Treatment with trinitrobenzene sulfonic acid induced significant cholestasis and caused translocation of immunostaining for 7H6, but not that for ZO-1, to the cytoplasm and diminished immunostaining for mrp2 on the canaliculus membrane [6].
• The effects of polymyxin B, penicillin G, or metronidazole on immunostaining for 7H6, ZO-1, mrp2, and cholestasis were investigated [6].
• Taurine supplementation induces multidrug resistance protein 2 and bile salt export pump expression in rats and prevents endotoxin-induced cholestasis [7].

Biological context of Abcb4

• Cholestasis induces down-regulation of multidrug resistance protein 2 (Mrp2, symbol Abcc2), which is localized to the canalicular membrane [8].
• In summary, the increase in Mrp2 protein after microsomal enzyme induction is responsible for increased biliary DBSP excretion [9].
• Transient transfection assays with reporter vectors containing unidirectionally deleted 5'-flanking regions using H4IIE cells indicate that two different sequences of 17 and 37 bases comprising a Y-Box and a GC-Box are required for mrp2 gene basal expression [2].
• To further examine the substrate specificity of Mrp2, we examined the effects of bile acid sulfates on the biliary excretion of phenolphthalein sulfate in rats [10].
• (2) Bsep- and Mrp2-specific vesicles participate in the short-term osmoregulation of canalicular secretion, however, a cause-effect relationship between bile salt excretion and transporter localization remains to be established [11].

Anatomical context of Abcb4

• Our results indicate that phalloidin induces marked alterations of the hepatocyte canalicular architecture and a loss of Mrp2 together with other proteins from the canalicular membrane [1].
• Confocal immunofluorescent microscopy showed asynchronous appearance of Bsep and Mrp2 proteins during development but their colocalization in the bile canaliculi once each one is expressed [12].
• Expression and immunolocalization of multidrug resistance protein 2 in rabbit small intestine [13].
• The present study demonstrates exclusive localization of Mrp2 to the brush-border (apical) membrane of villi, decreasing in intensity from the villus tip to the crypts [13].
• In immunoblot analysis of crude membranes of various rabbit tissues, Mrp2 was only found in small intestine, kidney and liver [13].

Associations of Abcb4 with chemical compounds

• Canalicular multispecific organic anion transporter/multidrug resistance protein 2 mediates low-affinity transport of reduced glutathione [14].
• Lipopolysaccharide (LPS) induces hepatocellular down-regulation and endocytic retrieval of multidrug resistance protein 2 (Mrp2, Abcc2) [15].
• Endotoxin downregulates hepatic expression of P-glycoprotein and MRP2 in 2-acetylaminofluorene-treated rats [16].
• PB and PCN also increased Mrp2 protein levels, but 3MC and BaP did not [17].
• The data indicate that there are Mrp2-independent mechanisms in the rat for biliary excretion of dicarboxylate organic anions related to biliverdin [18].

Other interactions of Abcb4

• Furthermore, in vivo administration of AAF, which maximally induces PGP does not induce MRP2 [16].

Analytical, diagnostic and therapeutic context of Abcb4

• In line with the immunofluorescence analysis, immunoblots indicated a loss of Mrp2 and P-glycoproteins from the canalicular membrane and a 3- and 4.6-fold increase of these transport proteins in the microsomal fraction, respectively [1].
• Expression of PGP and MRP2 was analyzed on Westerns and by RT-PCR in livers obtained from endotoxin and control groups [16].
• Under hyperosmolar perfusion Mrp2, but not the canalicular protein dipeptidylpeptidase IV, was found inside the cells, as shown by double immunofluorescence and confocal laser scanning microscopy [19].
• Sequence analysis and functional characterization of the 5'-flanking region of the rat multidrug resistance protein 2 (mrp2) gene [2].
• RESULTS: Intestinal Mrp2 and Abcg5/Abcg8 mRNA expression remarkably decreased 24 h after bile duct ligation (43% and 61%/54% of sham operation) and recovered 72 h after bile duct ligation (103% and 95%/83% of sham operation) [20].

References