Induction of the Multidrug Resistance-Associated Protein Family of Transporters by Chemical Activators of Receptor-Mediated Pathways in Mouse Liver

Abstract

ABSTRACT:The multidrug resistance-associated proteins ( , -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␣-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␣, 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.

Influence of polymorphisms of ABCB1 and ABCC2 on mRNA and protein expression in normal and cancerous kidney cortex

“…However, splitting the data for the different histological subtypes, it became obvious that this difference was only owing to clear-cell carcinomas, but not for non-CCRCC tissue. There is some evidence that xenobiotics may interfere with signaling pathway involved in the activation of P-gp and MRP2 [27][28][29] or lead to an elevated expression via PXR-transactivating elements. 27,30 However, the lower ABCB1 expression of CCRCC tissue or ABCC2 in non-CCRCC could be also the consequence of altered gene regulation or low cell differentiation and not necessarily causative in the genesis of cancer.…”

Oxidative and electrophilic stress induces multidrug resistance–associated protein transporters via the nuclear factor-E2–related factor-2 transcriptional pathway

“…OPZ and BHA induced Nqo1 more than 3-fold and 6-fold, respectively, in WT mice, but this induction was almost completely attenuated in Nrf2-null mice; this indicated that the treatments were inducing via the Nrf2 pathway, similar to previous observations. 25 OPZ and BHA produced modest increases in Mrp2 mRNA expression, and although the expression tended to be attenuated in Nrf2-null mice, the decrease was not statistically significant (Fig. 5).…”

“…Previous work from this laboratory 25 has suggested that Nrf2 activation can lead to Mrp up-regulation, and there is further evidence in vitro that Mrp2 may be regulated by Nrf2. 26 The purpose of this study was to determine whether Mrp2, Mrp3, and Mrp4 are induced (1) in the absence of GSH or (2) after a treatment with Nrf2-activating chemicals in 2 mouse models of Nrf2 activation and (3) whether Mrp induction under these conditions is mediated via the Nrf2-transcriptional pathway.…”

Tanshinone I Activates the Nrf2-Dependent Antioxidant Response and Protects Against As(III)-Induced Lung Inflammation In Vitro and In Vivo

“…Conjugating enzymes, including glutathione S-transferases (GSTs) and UDP-glucuronosyltransferase, facilitate the removal of toxic and carcinogenic chemicals by increasing their solubility and excretion (19,21,28). Transporters, such as multidrug resistance proteins and p-glycoproteins, are important in the uptake and removal of xenobiotics (18,37,51,58).…”