Disease relevance of Abcc2

• Cholestasis induces down-regulation of multidrug resistance protein 2 (Mrp2, symbol Abcc2), which is localized to the canalicular membrane [1].
• CONCLUSIONS: Oatp2 and Mrp2 expression is decreased in fatty liver and may impair metabolism and biliary secretion of numerous xenobiotics [2].
• Extended treatment of rats with fusidate (100 micromol/kg body weight, three times daily i.p. for 3 days) reduced hepatic Mrp2 protein levels by 61% (P<0.001) [3].
• We demonstrated that tienilic acid, a diuretic drug withdrawn from the market because of hepatic failure, enhanced hyperbilirubinemia in Eisai hyperbilirubinuria rats (EHBR) with a defect of canalicular multidrug resistance-associated protein 2 (Mrp2) [4].
• We described that both hepatocyte TJs and the canalicular multispecific organic anion transporter were altered and that gut-derived endotoxin levels in the portal blood were increased in this rat colitis model [5].

High impact information on Abcc2

• IL-1 beta treatment of primary hepatocytes reduced Mrp2 and RXR alpha expression [6].
• CONCLUSIONS: Organ-specific regulation of Mrp2 expression in obstructive cholestasis is associated with cytokine-dependent alterations in RAR alpha:RXR alpha nuclear receptors [6].
• This was temporally associated with down-regulation of liver RAR alpha:RXR alpha nuclear protein levels and binding to the Mrp2 promoter cis element [6].
• RESULTS: Bsep-expressing Sf9 cell vesicles showed ATP-dependent transport of numerous monoanionic bile salts with similar Michaelis constant values as in cLPM vesicles, whereas several known substrates of the multispecific organic anion transporter Mrp2 were not transported by Bsep [7].
• In contrast, protein and mRNA expression of both the canalicular ATP-dependent bile salt export pump (Bsep) and the multiorganic anion transporter Mrp2 remained unchanged or were slightly increased during liver regeneration, but also returned to control values 7-14 days after partial hepatectomy [8].

Chemical compound and disease context of Abcc2

• Cholestasis secondary to cyclosporine A could be related to reduction in mRNA expression of GSH synthesising enzymes and Mrp2, leading to reduced protection against oxidative stress and reduced bile acid-independent bile flow [9].
• Impaired activity of the bile canalicular organic anion transporter (Mrp2/cmoat) is not the main cause of ethinylestradiol-induced cholestasis in the rat [10].
• Therefore, the effect of taurine-conjugated UDCA (TUDCA) was studied in the experimental model of taurolithocholic acid (TLCA)-induced cholestasis on bile flow, hepatobiliary exocytosis, distribution of PKC isoforms, and density of the apical conjugate export pump, Mrp2, in canalicular membranes [11].
• We conclude that severe glutathione depletion induces cholestasis by a retrieval of Mrp2, but not of DPPIV from the canalicular membrane [12].
• Lipopolysaccharides (LPS) induces intrahepatic cholestasis and canalicular multispecific organic anion transporter (CMOAT/MRP2) plays a central role in hepatic bilirubin transport [13].

Biological context of Abcc2

• We have described the internalization of multidrug resistance-associated protein 2/ATP-binding cassette transporter family 2 (Mrp2/Abcc2), a biliary transporter involved in bile-salt-independent bile flow, under ethacrynic acid (EA)-induced acute oxidative stress in rat liver [14].
• Furthermore, Bsep and Mrp2 protein levels were maintained at about 50%, while the Mrp2 mRNA showed a transient up-regulation to 154% at 24 and 48 hours [15].
• Mrp2 mRNA was stable in pregnancy and postpartum, whereas Mrp2 protein expression decreased significantly in pregnancy, but returned to control levels postpartum [16].
• Role of glycosylation in trafficking of Mrp2 in sandwich-cultured rat hepatocytes [17].
• We conclude that the pharmacokinetics of MMF are comparable in Mrp2-deficient rats receiving either CsA or Tac as co-medication [18].

Anatomical context of Abcc2

• Unaltered expression of Bsep and Mrp2 provides a potential molecular mechanism for regenerating liver cells to maintain or even increase bile secretion expressed per weight of remaining liver [8].
• Canalicular Mrp2 decreased and amounted to 34% of normal after bile duct ligation for 72 hours [1].
• Expression of Mrp2 protein determined by Western analysis of total liver homogenate decreased to 50% of control levels in pregnant rats, consistent with studies using plasma membranes [19].
• We found previously that expression of multidrug resistance-associated protein (MRP) 3 is induced in a mutant rat strain (Eisai hyperbilirubinemic rats) whose canalicular multispecific organic anion transporter (cMOAT/MRP2) function is hereditarily defective and in normal Sprague-Dawley (SD) rats after ligation of the common bile duct [20].
• 2. Results from in vitro studies in microsomes showed that the hepatic intrinsic clearance (CLint) for the oxidative metabolism of gemfibrozil was slightly higher (1.5-fold) in male TR- rats, which are deficient in Mrp2, than in wild-type Wistar rats, whereas CLint for glucuronidation was similar in both strains [21].

Associations of Abcc2 with chemical compounds

• Lipopolysaccharide (LPS) induces hepatocellular down-regulation and endocytic retrieval of multidrug resistance protein 2 (Mrp2, Abcc2) [22].
• Impaired bile salt-independent bile flow in obese rats was associated with a 50% reduction of biliary secretion of the Mrp 2 model-substrates glutathione disulfide and S-(2,4-dinitrophenyl)glutathione [2].
• Fusidate inhibited the ATP-dependent transport of the Mrp2 substrates 17beta-glucuronosyl estradiol and leukotriene C4, and the transport of cholyltaurine by Bsep with Ki values of 2.2+/-0.3, 7.6+/-1.3, and 5.5+/-0.8 microM, respectively [3].
• Mrp2 expression was not influenced by DHEA treatment [23].
• Metabolism and disposition of gemfibrozil in Wistar and multidrug resistance-associated protein 2-deficient TR- rats [21].

Physical interactions of Abcc2

• Because Mrp3 transports TC and its expression is induced on the basolateral membrane of Mrp2-deficient rats, the enhanced sinusoidal efflux of TC in EHBR may be accounted for, at least partially, by the increased expression of Mrp3 [24].
• To examine whether P-glycoprotein has a role in canalicular transport of organic anions in addition to the canalicular multispecific organic anion transporter, we studied the effect of colchicine, a vesicular transport inhibitor, and phenothiazine to increase P-glycoprotein expression on biliary excretion of various organic anions in rats [25].

Other interactions of Abcc2

• In Mrp2-deficient mutant rat liver, the Mrp3 protein expression was most enhanced and its zonation was lost [1].
• Messenger RNA (mRNA) levels of transporters and binding activities as well as nuclear protein levels of Ntcp, Oatp2, and Mrp2 transactivators were determined 20 to 24 hours later [26].
• Our data show that in the liver of both strains, exposure to a hypotonic medium stimulates DOX excretion, presumably by activation of P-gp and mrp2 during RVD [27].
• In contrast, CDF appears to be taken up by Oatp-mediated transport into rat hepatocytes and effluxed via Mrp2 into bile and via Mrp3 into sinusoidal blood [28].
• Therefore, Bcrp1 has an important role in extruding glucuronide and sulfate conjugates formed in enterocytes into the intestinal lumen, whereas Mrp2 is responsible for the efflux of some glucuronide conjugates [29].

Analytical, diagnostic and therapeutic context of Abcc2

• Confocal immunohistochemistry showed that Mrp2 expression was confined to the canalicular membrane in both control and pregnant rats and was not detectable in intracellular compartments [19].
• Western blot studies revealed increased expression of Mrp2 in response to SL whereas AE2 content remained unchanged [30].
• Enhanced activity and expression of Mrp2 was confirmed by analyzing the excretion rate of dinitrophenyl S-glutathione, an exogenous substrate of Mrp2, in isolated hepatocytes and by immunofluorescence microscopy, respectively [30].
• SDR liver preperfused with hyperosmolar buffer (405 mosmol/L) for 30 min induced internalization of Mrp2 without changing the basal GSH level, while elimination of hepatic GSH by 300 microM EA perfusion was significantly delayed thereafter [31].
• After hypophysectomy, Mrp2 mRNA was markedly reduced and the effects of estrogens and testosterone on Mrp2 were prevented, supporting the role of pituitary hormones in controlling Mrp2 expression [32].

References