NR1I2-NR1I3 - -nuclear receptor subfamily 1 group I member | Elisa - Clia - Antibody - Protein

Background

NR1I2 and NR1I3 are part of the nuclear receptor subfamily 1 group I, encompassing key regulators in the metabolism and detoxification of endogenous and exogenous substances. The nuclear receptor family includes ligand-activated transcription factors essential for gene expression regulation. NR1I2, also known as the pregnane X receptor (PXR), and NR1I3, known as the constitutive androstane receptor (CAR), play crucial roles in the body's defense against potentially harmful compounds by regulating the expression of genes involved in drug metabolism and disposition. These receptors are predominantly expressed in the liver and intestines, aligning with their primary roles in xenobiotic metabolism.

Protein Structure

• NR1I2 (PXR):
• DNA-Binding Domain (DBD): Comprising two zinc finger motifs, this domain facilitates specific binding to DNA sequences called response elements in target gene promoters.
• Ligand-Binding Domain (LBD): The LBD in PXR is highly flexible, allowing it to bind to a wide range of ligands, including steroids, antibiotics, and herbal compounds.
• Activation Function (AF) Domain: Located in the C-terminal, this domain interacts with coactivators and corepressors to modulate transcriptional activity.
• NR1I3 (CAR):
• DNA-Binding Domain (DBD): Similar to PXR, CAR's DBD contains zinc finger motifs that bind to specific response elements in DNA.
• Ligand-Binding Domain (LBD): The LBD in CAR binds to various endogenous and exogenous compounds, influencing its activation state.
• Activation Function (AF) Domain: This domain is crucial for recruiting transcriptional coactivators necessary for gene regulation.

Classification and Subtypes

NR1I2 and NR1I3 are classified under the nuclear receptor subfamily 1 group I, distinguished by their roles in xenobiotic metabolism:

• NR1I2 (PXR): Responds to a diverse array of ligands, regulating genes involved in detoxification.
• NR1I3 (CAR): Activates or represses genes associated with drug metabolism and energy homeostasis in response to different ligands.

Function and Biological Significance

• Detoxification: Both PXR and CAR are pivotal in the body's detoxification processes, regulating the expression of cytochrome P450 enzymes, which are essential for drug metabolism.
• Homeostasis: They maintain metabolic homeostasis by controlling the expression of genes involved in bile acid synthesis, lipid metabolism, and glucose homeostasis.
• Drug-Drug Interactions: By regulating drug-metabolizing enzymes, PXR and CAR play significant roles in drug-drug interactions, influencing the efficacy and toxicity of pharmaceuticals.
• Protective Roles: They protect against various xenobiotics and endogenous toxins by upregulating genes involved in their clearance.

Clinical Issues

• Drug Metabolism: Variations in PXR and CAR activity can lead to altered drug metabolism, affecting drug efficacy and safety. Polymorphisms in these receptors are linked to differences in drug response among individuals.
• Liver Diseases: Dysregulation of PXR and CAR is associated with liver diseases, including non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma.
• Endocrine Disruption: Environmental chemicals that activate PXR and CAR can lead to endocrine disruption, impacting hormone balance and reproductive health.
• Metabolic Disorders: Abnormal PXR and CAR signaling is implicated in metabolic disorders like obesity and diabetes due to their roles in lipid and glucose metabolism.

Summary

NR1I2 (PXR) and NR1I3 (CAR) are critical nuclear receptors in the detoxification and metabolism of various compounds. Their flexible ligand-binding domains allow them to respond to a wide range of substances, regulating genes crucial for drug metabolism and metabolic homeostasis. Dysregulation of these receptors can lead to significant clinical issues, including altered drug response, liver diseases, and metabolic disorders. Understanding the mechanisms governing PXR and CAR function is essential for developing therapeutic strategies to mitigate adverse drug reactions and treat related diseases.