What is a PXR agonist?
Pregnane X receptor (PXR) is an orphan nuclear receptor that regulates the expression of genes encoding drug-metabolizing enzymes and transporters. In addition to affecting drug metabolism, potent and selective PXR agonists may also have therapeutic potential by removing endogenous and exogenous toxins.
How does PXR work?
Function. PXR is a nuclear receptor whose primary function is to sense the presence of foreign toxic substances and in response up regulate the expression of proteins involved in the detoxification and clearance of these substances from the body.
What activates PXR?
PXR activation is ligand dependent; following ligand binding, PXR forms a heterodimer with the retinoid X receptor (RXR) that binds to PXR response elements, located in the 5′-flanking regions of PXR target genes, resulting in their transcriptional activation.
What is PXR gene?
Pregnane X receptors (PXRs) are nuclear receptors that regulate the expression of CYP3A genes, generating key enzymes involved in xenobiotic metabolism. PXRs also help regulate the induction of P-gp. PXRs are highly expressed in the liver, small intestine and colon.
Where is PXR located?
Human PXR (hPXR) is the product of the NR1I2 gene, which is located on chromosome 3, locus 3q11–q13. 3. The NR1I2 gene comprises 10 exons separated by nine intronic regions (Hustert et al., 2001; Zhang et al., 2001).
What is PXR and RXR?
In its heterodimeric form with the retinoid X receptor (RXR), the pregnane X receptor (PXR) plays an essential role in controlling the mammalian xenobiotic response and mediates both beneficial and detrimental effects.
Is PXR a transcription factor?
Pregnane X receptor (PXR) is now accepted as a master transcription factor of xenobiotic- and drug-inducible expression of key genes that encode members of the phase I and phase II metabolic enzymes and drug transporters.
Why are nuclear receptors important?
Nuclear receptors have the ability to directly bind to DNA and regulate the expression of adjacent genes; hence these receptors are classified as transcription factors. As a consequence, nuclear receptors play key roles in both embryonic development and adult homeostasis.
What is nuclear receptor example?
Nuclear receptors are a family of ligand-regulated transcription factors that are activated by steroid hormones, such as estrogen and progesterone, and various other lipid-soluble signals, including retinoic acid, oxysterols, and thyroid hormone (Mangelsdorf et al. 1995).
Which is an agonist of the pregnane X receptor?
Meclizine, a pregnane X receptor agonist, is a direct inhibitor and mechanism-based inactivator of human cytochrome P450 3A Meclizine is an agonist of human pregnane X receptor (PXR).
How does meclizine work on the pregnane X receptor?
Meclizine is an agonist of human pregnane X receptor (PXR). It increases CYP3A4 mRNA expression, but decreases CYP3A-catalyzed testosterone 6β-hydroxylation in primary cultures of human hepatocytes, as assessed at 24h after the last dose of meclizine.
Which is an agonist of PXR and car?
PXR and CAR induce enzymes, such as CYP2B and CYP3A family members, responsible for the metabolism of steroid and thyroid hormones, thus altering normal physiological function. For example, chlordane is an agonist of the human and rodent CAR, as is lindane.
Is the PXR a steroid or xenobiotic receptor?
PXR is another member of the nuclear receptor superfamily of ligand-activated transcription factors, also known as the steroid and xenobiotic receptor or pregnane-activated receptor.