Induction of the multidrug resistance-associated protein family of transporters by chemical activators of receptor-mediated pathways in mouse liver

The multidrug resistance-associated proteins (Mrp) are ATP-dependent transporters that export a variety of conjugated and unconjugated compounds out of cells. There are nine identified Mrp transporters in humans, with murine orthologs for all except Mrp8. Because nuclear receptors mediate induction of phase I enzymes, Mrp transporter expression might be similarly regulated by these receptors to coordinate metabolism and export of chemicals from liver. To test the hypothesis that Mrp expression may be coordinately regulated with phase I enzyme expression in liver, 15 different compounds were given representing known transcriptionally mediated pathways: aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), constitutive androstane receptor (CAR), peroxisome proliferator-activated receptor alpha (PPAR alpha), and nuclear factor-E2-related factor 2 (Nrf2). Each of these compounds induced expression of their respective target enzyme in liver, demonstrating that the chemical regimens were effective. The AhR ligands [2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polychlorinated biphenyl 126 (PCB126), and beta-naphthoflavone] induced Mrp2, -3, -5, and -6 mRNA expression. The CAR activator 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) induced Mrp2, -3, -4, -6, and -7 mRNA expression. Mrp3 was also induced by two other CAR activators phenobarbital and diallyl sulfide, two PXR ligands, pregnenalone-16 alpha-carbonitrile and spironolactone, and the PPAR ligands clofibrate, ciprofibrate, and diethylhexylphthalate. The Nrf2 activators (butylated hydroxyanisole, oltipraz, and ethoxyquin) induced Mrp2 -6. In conclusion, a variety of mechanisms are suggested for Mrp3 induction, including AhR, CAR, PXR, PPAR alpha, and Nrf2, whereas on a whole, a predominant role for AhR and Nrf2 in hepatic induction of the Mrp family was observed. Thus, these specific transcription factors are implicated in regulation of both drug metabolism and efflux transport.