Regulation Of Transporter Expression

Transporter expression can be regulated transcriptionally in response to drug treatment and pathophysiological conditions, resulting in induction or down-regulation of transporter mRNAs. A number of nuclear receptors form heterodimers with the 9-cis-retinoic acid receptor (RXR) in regulating drug-metabolizing enzymes and transporters. Such receptors include pregnane X receptor (PXR/NR1I2), constitutive androstane receptor (CAR/NR1I3), farnesoid X receptor (FXR/NR1H4), peroxisome proliferator-activated receptor a (PPARa), and retinoic acid receptor (RAR). Except for CAR, these are ligand-activated nuclear receptors that, as heterodimers with RXR, bind specific elements in the enhancer regions of target genes. CAR has constitutive tran-scriptional activity that is antagonized by inverse agonists such as androstenol and androstanol and induced by barbiturates. PXR (SXR in humans) is activated by synthetic and endogenous steroids, bile acids, and drugs such as clotrimazole, phenobarbital, rifampin, sulfinpyrazone, ritonavir, carbamazepine, phenytoin, sulfadimidine, taxol, and hyperforin (a constituent of St. John's wort). Table 2—1 summarizes the effects of drug activation of nuclear receptors on transporter expression. There is an overlap of substrates between CYP3A4 and P-glycoprotein, and PXR mediates coinduction of CYP3A4 and P-glycoprotein, supporting their cooperation in efficient detoxification.

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