New Insights on the Xenobiotic-Sensing Nuclear Receptors in Liver Diseases – CAR and PXR-

Abstract

The xenobiotic receptors CAR and PXR constitute two important members of the NR1I nuclear receptor family. They function as sensors of toxic byproducts derived from the endogenous metabolism and of exogenous chemicals, in order to enhance their elimination. They regulate numerous genes which are involved in drug and xenobiotic metabolism, including Phase I (cytochrome P450), Phase II (conjugation catalyzed by sulfotransferases, glucuronosyltransferases and glutathione S-transferases), and transporters (multidrug resistance proteins, multidrug resistance-associated proteins, and organic anion-transporting polypeptides). Although CAR and PXR were initially characterized as xenosensors, it is now evident that CAR and PXR also trigger pleiotropic effects on physiological or pathological functions. Recent studies have shown that the activation of CAR and PXR alters lipid metabolism, glucose homeostasis, and inflammation. Therefore, in addition to regulating drug elimination pathways, they also play important roles in regulating metabolic pathways. As a result, these receptors may be closely associated with the pathogenesis of many diseases. However, the pathophysiological roles of CAR and PXR are not fully understood. The purpose of this review is to discuss the physiological and pathological roles of CAR and PXR in liver diseases.

Cryptotanshinone Ameliorates Hepatic Normothermic Ischemia and Reperfusion Injury in Rats by Anti-mitochondrial Apoptosis

“…Kakizaki et al identified the protective effect of inhibition of p38 on I/R-induced liver apoptosis in rats. 35) In deoxycholic acid-induced hepatocyte apoptosis, inhibition of p38 MAPK is one antiapoptotic mechanism.…”

Activation of Pregnane X Receptor (PXR) and Constitutive Androstane Receptor (CAR) by Herbal Medicines

“…Future efforts in detailed chemical analysis will also be needed to identify the specific chemical constituent(s) responsible for the PXR/CARactivating effects of the whole extract. Overall, with the appreciation that PXR and CAR may serve as potential therapeutic targets (10,11), the discovery of specific herbal medicines and some of their chemical constituents as in vitro modulators of PXR and CAR will provide a basis for targeted pharmacodynamic studies in the future.…”

“…Recent studies have indicated that these receptors play a regulatory role in various physiological and pathophysiological processes, such as lipid metabolism, glucose homeostasis, and inflammatory response (10). Collectively, the available evidence suggests that PXR and CAR may be useful targets for pharmaco-logical intervention in various conditions, including hepatic steatosis, cholestatic liver disease, hyperbilirubinemia, osteoporosis, and inflammatory diseases (10,11).…”

Role of Constitutive Androstane Receptor in Toll-Like Receptor-Mediated Regulation of Gene Expression of Hepatic Drug-Metabolizing Enzymes and Transporters

“…The modulation of DMEs and transporters at the transcriptional level is regulated by basal transcription factors as well as the xenobiotic nuclear receptors (NRs), pregnane X receptor (PXR) and constitutive androstane receptor (CAR). The NRs heterodimerize with retinoid X receptor a to bind to the promoter regions of the target genes (Mangelsdorf and Evans, 1995;Tien and Negishi, 2006;Kakizaki et al, 2008;Shen and Kong, 2009;Zordoky and El-Kadi, 2009). The molecular mechanism by which DMEs and transporters are downregulated during inflammation is not fully understood.…”