Analysis of the in vivo functions of Mrp3.
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 ( approximately 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.
Belinsky
Martin G
MG
Medical Science Division, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
Dawson
Paul A
PA
Shchaveleva
Irina
I
Bain
Lisa J
LJ
Wang
Renxue
R
Ling
Victor
V
Chen
Zhe-Sheng
ZS
Grinberg
Alex
A
Westphal
Heiner
H
Klein-Szanto
Andres
A
Lerro
Anthony
A
Kruh
Gary D
GD
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D020868:Gene Silencing; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D011247:Pregnancy
D001647:Bile Acids and Salts; D005047:Etoposide; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009943:Organophosphorus Compounds; C114462:multidrug resistance-associated protein 3; C061400:etoposide phosphate