CAR, Driving into the Future

Abstract

The nuclear orphan receptor CAR is active in the absence of ligand with the unique capability to be further regulated by activators. A number of these activators, including phenobarbital, do not directly bind to the receptor. Considered a xenobiotic sensing receptor, CAR transcriptionally modifies the expression of genes involved in the metabolism and elimination of xenobiotics and steroids in response to these compounds and other cellular metabolites. Its hepatic expression pattern endows the liver with the ability to protect against not only exogenous but also endogenous insults. The mechanism of CAR activation is complex, involving translocation from the cytoplasm to the nucleus in the presence of activators, followed by further activation steps in the nucleus. Although this mechanism remains under investigation, we have summarized here the cellular signaling pathways elucidated so far and speculate on the mechanism by which CAR activators regulate gene expression through this network.

Di-(2-ethylhexyl)-phthalate (DEHP) activates the constitutive androstane receptor (CAR): A novel signalling pathway sensitive to phthalates

“…It remains to be established whether DEHP or one if its metabolite other than MEHP directly binds to mouse and/or human CAR. CAR (Nr1i3) was first described as a xenobiotic-sensing nuclear receptor that regulates the expression of hepatic enzymes and transporters involved in xenobiotic metabolism [57]. It is closely related to PXR (Nr1i2) and these receptors share both ligands [58] and target genes [59].…”

Transcription coactivator peroxisome proliferator-activated receptor-binding protein/mediator 1 deficiency abrogates acetaminophen hepatotoxicity

“…2 A). Treatment with either PB or TCPOBOP for 3 days resulted in the induction of hepatic CYP3A11, CYP1A2, and CYP2B10 mRNAs in wild-type mice (16,27) but not in PBP LivϪ/Ϫ animals. In CAR-null mice, CYP2B10 induction is abolished because of the deletion of this gene in all cells (20,21).…”

“…CAR mediates the response evoked by a class of xenobiotics referred to as the ''PB-like inducers'' (16,26). Short-term treatment with either PB or TCPOBOP increased liver mass in wild-type PBP ϩ/ϩ mice but not in PBP LivϪ/Ϫ mice (Fig.…”

“…In essence, the absence of PBP in hepatocytes in vivo mimics the absence of PPAR␣ (15), indicating that both PPAR␣ and PBP are required for PPAR␣-regulated gene expression in hepatocytes. Here, we report the role of PBP in the action of constitutive androstane (active) receptor (CAR) and in acetaminophen-induced liver injury (16). Acetaminophen (APAP; also known as paracetamol, N-acetyl-p-aminophenol, and 4Ј-hydroxyacetanilide) overdose is the leading cause of acute liver failure in the United States (17).…”

Phenobarbital Confers its Diverse Effects by Activating the Orphan Nuclear Receptor Car

“…Looking back these 38 years, I realize that PB has always been a subject of my research. Therefore, you can well imagine the deep sense of satisfaction/fulfillment I felt when it was observed that mice lacking the nuclear receptor CAR gene will sleep longer than normal mice following PB administration (Swales and Negishi, 2004). Here we describe a short history of how CAR emerged as a coordinate factor that regulates diverse liver functions (Fig.…”