An update on the constitutive androstane receptor (CAR)

Abstract

The constitutive androstane receptor (CAR; NR1I3) has emerged as one of the main drug- and xenobiotic-sensitive transcriptional regulators. It has a major effect on the expression of several oxidative and conjugative enzymes and transporters, and hence, CAR can contribute to drug/drug interactions. Novel functions for CAR are also emerging: it is able to modulate the metabolic fate of glucose, lipids, and bile acids, and it is also involved in cell-cell communication, regulation of the cell cycle, and chemical carcinogenesis. Here, we will review the recent information available on CAR and its target gene expression, its interactions with partner proteins and mechanisms of action, interindividual and species variation, and current advances in CAR ligand selectivity and methods used in interrogation of its ligands.

Chrysin, baicalein and galangin are indirect activators of the human constitutive androstane receptor (CAR)

“…2B), a result which corresponds with previous reports (Molnar et al, 2013;Moore et al, 2000). On the other hand some inhibition of CAR by phenobarbital was observed at 1000 mM concentration.…”

“…At present, natural compounds such as artemisinin and its derivatives arteether and artemether; pyrethroids (e.g., permethrin, cypermethrin); flavonoids such as chrysin, baicalein and galangin, and diallyl sulfide derived from garlic, have been reported as activators of CAR (Burk et al, 2005(Burk et al, , 2012Molnar et al, 2013;Sueyoshi et al, 2011;Yao et al, 2011). In addition, numerous synthetic compounds have been demonstrated to activate CAR such as carbamate benfuracarb, organochlorines (e.g., methoxychlor), CITCO,FL81,octicizer,[1,5]benzothiazepine derivatives, and sulfonamides; and drugs (e.g., artemisinin derivatives, nevirapine, nicardipine, efavirenz, carbamazepine) (Anderson et al, 2011;Burk et al, 2012;Faucette et al, 2007;Kublbeck et al, 2011a,b;Lynch et al, 2013;Molnar et al, 2013;Yao et al, 2011).…”

“…It has been proposed in several independent animal studies that CAR activation may ameliorate glucose homeostasis and insulin sensibility in the treatment of type 2 diabetes (Dong et al, 2009;Gao et al, 2009). In addition, CAR activation reduces levels of lipoproteins and inhibits the expression of lipogenic genes in what might be a promising therapeutic intervention in the treatment of obesity (Dong et al, 2009;Gao and Xie, 2012;Jiang and Xie, 2013;Molnar et al, 2013).…”

“…Numerous compounds have been proposed as agonists, antagonists as well as inverse agonists for human CAR (Hernandez et al, 2009;Molnar et al, 2013). In contrast to other nuclear or steroid hormone receptors, CAR can be activated in both ligand binding domain (LBD)-dependent and independent (indirect) interactions (Moore et al, 2000).…”

“…*p < 0.05 -statistically significant difference compared to control (vehicle-treated) cells (ANOVA with a Bonferroni post hoc test). acetaminophen, bilirubin and phenobarbital) and the ligands which interact within its ligand binding domain (Molnar et al, 2013;Moore et al, 2000). Currently the only high-affinity agonist for human CAR is 6-(4-chlorophenyl) imidazo[2,1-b]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl) oxime (CITCO) (Maglich et al, 2003).…”