Disease relevance of Nr1i2

• Pregnenolone-16alpha-carbonitrile (PCN), a prototypical rodent CYP3A inducer and pregnane-X-receptor (PXR) ligand, stimulates the hepatic clearance of cardiac glycosides in newborn rats, which results in decreased toxicity of the cardiac glycosides [1].

High impact information on Nr1i2

• Thus, EDC-occupied PXR may regulate its specific gene expression through the receptor-coactivator interaction [2].
• In this paper, we demonstrated that phthalic acid and nonylphenol, endocrine-disrupting chemicals (EDCs), stimulated PXR-mediated transcription at concentrations comparable to those at which they activate estrogen receptor-mediated transcription using a transient reporter gene expression assay in COS-7 cells [2].
• These data suggest that EDCs may affect endocrine functions by altering steroid hormone metabolism through PXR [2].
• Endocrine disrupting chemicals, phthalic acid and nonylphenol, activate Pregnane X receptor-mediated transcription [2].
• In the yeast two-hybrid protein interaction assay, PXR interacted with two nuclear receptor coactivator proteins, steroid hormone receptor coactivator-1 and receptor interacting protein 140, in the presence of phthalic acid or nonylphenol [2].

Biological context of Nr1i2

• In this study, the gene expression of 40 CYPs and 2 orphan nuclear receptors for CYP inducers, that is, Nr1i2 (CYP3A subfamily inducible by PCN) and Nr1i3 (CYP2B subfamily inducible by PB), in pregnant rat's liver, fetal liver, and placenta was investigated at one time [3].
• In receptor transactivation assays, both CAR and PXR transcriptional activities were significantly enhanced by DDE [4].
• In contrast, RT-PCR analysis revealed marked down-regulation of the nuclear receptors RXRalpha, PXR, FXR, LXR, PPARalpha and CAR [5].
• Pregnane X receptor (PXR) is a nuclear receptor that regulates the expression of genes for cytochrome P450 3A (CYP3A), multidrug resistance 1 (MDR1), and organic anion-transporting peptide 2 (OATP2) [6].
• Such data indicate that AAF up-regulates CYP3A23 through PXR activation but does not require PXR for exerting its carcinogenic promoting properties based on inhibition of cell growth [7].

Anatomical context of Nr1i2

• Two PXR ligands induced UGT1A2, but only in duodenum [8].
• This pattern of gene regulation occurred in liver and small intestine independent of PXR, constitutive androstane receptor, or hepatic nuclear factor-4alpha expression, suggesting that other factors are involved in controlling the extent of coordinated gene expression in response to a PXR agonist [9].
• Rat hepatocytes were treated with clofibrate or PFDA individually, or along with PXR ligand pregnenolone 16alpha-carbonitrile (PCN), and the levels of PXR and CYP3A23 were determined by Western blots [10].
• The opposing effects of clofibrate and PFDA on the PCN-induced expression of CYP3A23 suggest that peroxisome proliferators likely increase the expression of PXR but differentially alter its ligand-dependent induction [10].

Associations of Nr1i2 with chemical compounds

• The expression of Nr1i2 gene was significantly elevated only in dam's liver of PCN group, while the expression of Nr1i3 gene showed no changes in all groups [3].
• However, bisphenol A, another EDC, had no effect on PXR-mediated transcription, although this chemical significantly enhanced ER-mediated transcription [2].
• These data support the idea that induction of hepatic 3A1 and 2B1 by DDE is mediated through the activation of CAR and PXR [4].
• Clofibrate and perfluorodecanoate both upregulate the expression of the pregnane X receptor but oppositely affect its ligand-dependent induction on cytochrome P450 3A23 [10].
• Oatp2 mRNA levels, determined by the bDNA technique, generally did not show a correlation with the altered oatp2 protein levels, e.g., among PXR ligands, only PCN increased oatp2 mRNA levels, but spironolactone and dexamethasone did not [11].

Other interactions of Nr1i2

• Induction of rat organic anion transporting polypeptide 2 by pregnenolone-16alpha-carbonitrile is via interaction with pregnane X receptor [12].
• These data suggest that glucocorticoid-inducible SULT2-40/41 gene expression occurs through a dual mechanism, whose components possibly involve the glucocorticoid receptor and the pregnane X receptor [13].

Analytical, diagnostic and therapeutic context of Nr1i2

• 2(S)-((3,5-bis(Trifluoromethyl)benzyl)-oxy)-3(S)phenyl-4-((3-oxo-1,2,4-triazol-5-yl)methyl)morpholine (L-742694) is a potent activator of the rat PXR and was characterized for its effects on hepatic and intestinal gene expression in female Sprague-Dawley rats by DNA microarray analysis [9].
• Results from electrophoretic mobility shift assays showed that the PXR-retinoid X receptor alpha heterodimer binds to the DR3-2 with the highest affinity, to the DR3-4 and DR3-1 with a lower affinity, and weakly or not at all to the DR3-3 [12].
• Oatp2 protein levels determined by Western blot were decreased 56 to 72% by the AhR ligands, increased 84 to 132% by the CAR ligands, and increased 230 to 360% by PXR ligands [11].
• We used mRNA differential display to define further the domain of genes under the control of PCN/PXR [14].

References