Role of CAR and PXR in xenobiotic sensing and metabolism

Abstract

Introduction The xenobiotic detoxification system, which protects the human body from external chemicals, comprises drug-metabolizing enzymes and transporters whose expressions are regulated by pregnane X receptor (PXR) and the constitutive androstane receptor (CAR). The progress made in a large number of recent studies calls for a timely review to summarize and highlight these key discoveries. Areas covered This review summarizes recent advances in elucidating the roles of PXR and CAR in the xenobiotic detoxification system and highlights the progress in understanding the regulation of PXR and CAR activity at the post-translational levels, as well as the structural basis for the regulation of these two xenobiotic sensors. Expert opinion Future efforts are needed to discover novel agonists and antagonists with species and isoform selectivity, to systematically understand the regulation of PXR and CAR at multiple levels (transcriptional, post-transcriptional, and post-translational levels) in response to xenobiotics exposure, and to solve the structures of the full-length receptors, which will be enabled by improved protein expression and purification techniques and approaches. In addition, more efforts will be needed to validate PXR and CAR as disease-related therapeutic targets and thus expand their roles as master xenobiotic sensors.

Fungus-Derived Neoechinulin B as a Novel Antagonist of Liver X Receptor, Identified by Chemical Genetics Using a Hepatitis C Virus Cell Culture System

“…Gene ontology (GO) enrichment analysis based on a mean log P value indicates that the GO terms such as drug metabolism, lipid metabolism, and hormone metabolism are significantly overrepresented among genes downregulated by NeoB ( Table 2). Many of the genes involved in these metabolic processes are regulated by transcription factors, including nuclear hormone receptors (46,47). Moreover, the HCV life cycle is known to be modulated by multiple nuclear hormone receptors such as peroxisome proliferator-activated receptor (PPAR), estrogen receptor (ER), and farnesoid X receptor (32,(48)(49)(50), leading us to question whether NeoB affected the function of nuclear hormone receptors that, in turn, modulate HCV replication.…”

CYP3A4 Gene Is a Novel Biomarker for Predicting a Poor Prognosis in Hepatocellular Carcinoma

“…Regarding the mechanisms underlying the downregulation of the CYP3A4 gene, the expression of the CYP3A4 gene was regulated by nuclear receptors, wellestablished xenobiotic sensors capable of binding to various structurally diverse chemicals, such as pregnane X receptor (PXR) (30) and constitutive androstane receptor (CAR) (30,31). Promoter hyper-methylation has been reported to result in repression of CAR and PXR expression, which induces the down-regulation of drug-metabolizing enzymes, including the CYP3A4 gene, in human pluripotent stem cellderived hepatocyte-like cells (32).…”

“…Ethical approval for all experimental protocols and study was obtained from the institutional review board at the Shizuoka Cancer Center (Authorization Number: [25][26][27][28][29][30][31][32][33]. Written informed consent was obtained from all patients enrolled in the study.…”

A short-term high fat diet increases exposure to midazolam and omeprazole in healthy subjects

“…[2] These nuclear receptors recognize endogenous and exogenous ligands and transduce these internal and environmental signals into upregulation or downregulation of target genes, including P450 genes. Experimental studies have revealed numerous ligands of PXR and CAR, such as certain drugs, lipids, bile acids, and hormones.…”