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Belinsky MG , Dawson PA , Shchaveleva I , Bain LJ , Wang R , Ling V , Chen ZS , Grinberg A , Westphal H , Klein-Szanto A , Lerro A , Kruh GD
Analysis of the in vivo functions of Mrp3
Molecular Pharmacology. 2005 ;68(1) :160-168
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Abstract
Multidrug resistance protein 3 (MRP3) is an ATP-binding cassette transporter that is able to confer resistance to anticancer agents such as etoposide and to transport lipophilic anions such as bile acids and glucuronides. These capabilities, along with the induction of the MRP3 protein on hepatocyte sinusoidal membranes in cholestasis and the expression of MRP3 in enterocytes, have led to the hypotheses that MRP3 may function in the body to protect normal tissues from etoposide, to protect cholestatic hepatocytes from endobiotics, and to facilitate bile-acid reclamation from the gut. To elucidate the role of Mrp3 in these processes, the Mrp3 gene (Abcc3) was disrupted by homologous recombination. Homozygous null animals were healthy and physically indistinguishable from wild-type mice. Mrp3-/- mice did not exhibit enhanced lethality to etoposide phosphate, although an analysis of transfected human embryonic kidney 293 cells indicated that the potency of murine Mrp3 toward etoposide (?2.0- to 2.5-fold) is comparable with that of human MRP3. After induction of cholestasis by bile duct ligation, Mrp3-/- mice had 1.5-fold higher levels of liver bile acids and 3.1-fold lower levels of serum bilirubin glucuronide compared with ligated wild-type mice, whereas significant differences were not observed between the respective sham-operated mice. Bile acid excretion, pool size, and fractional turnover rates were similar in Mrp3-/- and wild-type mice. We conclude that Mrp3 functions as an alternative route for the export of bile acids and glucuronides from cholestatic hepatocytes, that the pump does not play a major role in the enterohepatic circulation of bile acids and that the lack of chemosensitivity is probably attributable to functional redundancy with other pumps.
Notes
0026895X (ISSN) Cited By: 10; Export Date: 25 May 2006; Source: Scopus CODEN: MOPMA; DOI: 10.1124/mol.104.010587 Language of Original Document: English Correspondence Address: Kruh, G.D.; Medical Science Division; Fox Chase Cancer Center; 333 Cottman Avenue Philadelphia, PA 19111, United States; email: Gary.Kruh@fccc.edu Molecular Sequence Numbers: GENBANK: AF104943; Chemicals/CAS: etoposide, 33419-42-0; glucuronic acid, 36116-79-7, 576-37-4, 6556-12-3; multidrug resistance protein 3, 231947-64-1, Bile Acids and Salts; etoposide phosphate, 117091-64-2; Etoposide, 33419-42-0; multidrug resistance-associated protein 3; Multidrug Resistance-Associated Proteins; Organophosphorus Compounds References: Belinsky, M.G., Bain, L.J., Balsara, B.B., Testa, J.R., Kruh, G.D., Characterization of MOAT-C and MOAT-D, new members of the MRP/cMOAT subfamily of transporter proteins (1998) J Natl Cancer Inst, 90, pp. 1735-1741; Bohan, A., Chen, W.S., Denson, L.A., Held, M.A., Boyer, J.L., Tumor necrosis factor ?-dependent up-regulation of Lrh-1 and Mrp3(Abcc3) reduces liver injury in obstructive cholestasis (2003) J Biol Chem, 278, pp. 36688-36698; Chen, F., Ma, L., Dawson, P.A., Sinal, C.J., Sehayek, E., Gonzalez, F.J., Breslow, J., (...), Shneider, B.L., Liver receptor homologue-1 mediates species- and cell line-specific bile acid-dependent negative feedback regulation of the apical sodium-dependent bile acid transporter (2003) J Biol Chem, 278, pp. 19909-19916; Chen, Z.-S., Lee, K., Kruh, G.D., Transport of cyclic nucleotides and estradiol 17-?-D-glucuronide by multidrug resistance protein 4. 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