Constitutive androstane receptor (CAR) (CAR)

NR1I3, commonly known as the Constitutive Androstane Receptor (CAR), is a member of the nuclear receptor superfamily that acts as a key sensor for xenobiotics and endobiotics [3, 7]. Primarily expressed in the liver, CAR regulates the expression of a broad array of genes involved in drug metabolism and transport, making it a master regulator of detoxification [1, 11]. Unlike many other nuclear receptors, CAR is constitutively active in the absence of ligands and is sequestered in the cytoplasm until activated by direct binding or indirect signaling, such as by phenobarbital [3, 13]. Beyond its role in drug clearance, CAR is increasingly recognized for its involvement in energy homeostasis, lipid and glucose metabolism, and cell proliferation [7, 11]. Therapeutically, modulating CAR activity offers potential for treating metabolic disorders like non-alcoholic fatty liver disease (NAFLD) and managing hyperbilirubinemia [2, 11]. However, its ability to induce a wide range of metabolic enzymes poses significant risks for drug-drug interactions and species-specific toxicities, such as rodent-specific liver tumor promotion [4, 10].

Other names

NR1I3CAR1MB67Nuclear receptor subfamily 1 group I member 3Constitutive activator of retinoid responseConstitutive active receptorConstitutive active responseOrphan nuclear hormone receptor

The constitutive androstane receptor (CAR) functions as a transcription factor that, upon activation by direct ligand binding or indirect signaling, translocates from the cytoplasm to the nucleus [3, 13]. In the nucleus, it forms a heterodimer with the Retinoid X Receptor (RXR) and binds to specific DNA response elements, such as the phenobarbital-responsive enhancer module (PBREM), to induce the transcription of genes encoding Phase I and II drug-metabolizing enzymes (e.g., CYP2B6, CYP3A4) and Phase III transporters (e.g., MRP2) [2, 4, 5].