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.