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Decreased hepatic breast cancer resistance protein expression and function in multidrug resistance-associated protein

Wei Yue1, Jin Kyung Lee, Koji Abe

  • 1Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Drug Metabolism and Disposition: the Biological Fate of Chemicals
|November 26, 2010
PubMed

Insights

Multidrug resistance-associated protein 2-deficient rats show reduced breast cancer resistance protein expression and function. This highlights the importance of considering both transporters when interpreting data from these rat models.

Area of Science:

  • Pharmacology
  • Drug Metabolism
  • Biochemistry

Background:

  • Multidrug resistance-associated protein 2 (Mrp2)-deficient (TR(-)) rats are used to study Mrp2's role in drug disposition.
  • Previous studies indicated decreased breast cancer resistance protein (Bcrp) in hepatocytes from TR(-) rats.

Purpose of the Study:

  • To characterize hepatic Bcrp expression and function in TR(-) rats.
  • To investigate the role of Bcrp in the disposition of nitrofurantoin and pitavastatin.

Main Methods:

  • Sandwich-cultured hepatocytes (SCH) and isolated perfused livers from TR(-) and wild-type (WT) rats were used.
  • Bcrp was knocked down using RNA interference.
  • Nitrofurantoin and pitavastatin served as Bcrp substrates.
  • TaqMan real-time RT-PCR was employed to measure Bcrp mRNA levels.

Main Results:

  • Bcrp protein and mRNA levels were significantly decreased in TR(-) rats but not in Eisai hyperbilirubinemic rats (EHBR).
  • Biliary excretion of nitrofurantoin, a Bcrp substrate, was reduced in TR(-) rats.
  • Bcrp knockdown in SCH reduced pitavastatin biliary excretion, and this reduction was also observed in TR(-) rats.

Conclusions:

  • Hepatic Bcrp expression and function are significantly decreased in TR(-) rats.
  • Both Bcrp and Mrp2 should be considered when interpreting data from TR(-) rats.
  • TR(-) and EHBR rats can help differentiate the roles of Mrp2 and Bcrp in drug disposition.

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