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TOXICOLOGY

Induction of Hepatic Transporters Multidrug Resistance-Associated Proteins (Mrp) 3 and 4 by Clofibrate Is Regulated by Peroxisome Proliferator-Activated Receptor

Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (J.S.M., L.M.A., J.E.M.); Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (J.M.M., C.D.K.); and Department of Pathology, VU Medical Center, Amsterdam, The Netherlands (G.L.S.)

Hepatic transporters play a vital role in the disposition of endogenous compounds and xenobiotics in the liver. The current study investigates the expression and regulation of hepatic efflux transporters in response to treatment with the peroxisome proliferator-activated receptor (PPAR) agonist clofibrate (CFB). Changes in mRNA and protein levels for several hepatic transporters were assessed in male CD-1 mice after 10 days of CFB dosing (500 mg/kg i.p.). Administration of CFB up-regulated mRNA levels for breast cancer resistance protein (Bcrp) and multidrug resistance-associated proteins 3 and 4 (Mrp3 and Mrp4, respectively). Western blot analysis confirmed that CFB enhances protein expression of liver Bcrp, Mrp3, and Mrp4 in CD-1 mice. To further characterize the regulation of these hepatic transporters, CFB-mediated changes in transporter mRNA levels were assessed in wild-type (sv/129) and PPAR-null male mice. Wild-type mice treated with CFB showed similar changes in mRNA levels for all of these transporters, whereas the PPAR-null mice did not. Although protein expression of Mrp3 and Mrp4 in the wild-type mice correlated well with changes in mRNA levels, Bcrp protein was not up-regulated by CFB treatment. These results show that PPAR activation by CFB coordinately regulates the hepatic efflux transporters Mrp3 and Mrp4. Induction of Mrp3 and Mrp4 by CFB may alter the disposition of toxicants and xenobiotics that are substrates for these transporters.

Address correspondence to: Dr. José E. Manautou, University of Connecticut Toxicology Program, Department of Pharmaceutical Sciences, School of Pharmacy, 69 North Eagleville Road, Unit 3092, Storrs, CT 06269. E-mail: jose.manautou{at}uconn.edu