PXR/SXR

From LipidomicsWiki

CAR AND PXR/SXR, THE XENOBIOTIC SENSORS
To protect the body against foreign chemicals (xenobiotics) and the buildup of toxic endogenous lipids, two nuclear receptors function in this metabolic cascade to regulate
detoxification and elimination. The constitutive androstane receptor (CAR) mediates the response to a narrow range of phenobarbital-like inducers (Tzameli and Mooore 2001). In
contrast, the human steroid xenobiotic receptor (SXR) or its rodent ortholog, the pregnane X receptor (PXR), respond to many prescription drugs, environmental contaminants, steroids, and toxic bile acids (Watkins et al. 2001). Consistent with their role as xenobiotic sensors, both receptors are expressed primarily in liver and small intestine.
Although CAR was initially proposed to be constitutively active, ligands with negative (androstanes) and positive (phenobarbital) effects were soon found (Tzamelin and Moore
2001). CAR binds to and activates the CYP2B promoter in response to phenobarbital-like molecules, the pesticide 1,4-bis[2-(3,5-dichlorpyridyloxyl)]- benzene (TCPOBOP), certain androgens, and the muscle relaxant drug zoxazolamine. Genetic disruption of the mouse CAR gene abolishes induced CYP2B expression, resulting in increased serum levels of nonmetabolized products (Wei et al. 2000). In terms of the metabolic cascade model, no cytoplasmic binding proteins have yet been identified that generally bind xenobiotics, although phenobarbital does induce the expression of ABCC3, a member of the multidrug resistancerelated protein subfamily (Kiuchi et al. 1998).
The CYP3A enzyme is responsible for metabolizing and clearing over 60% of clinically prescribed drugs, and its induction plays a pivotal role in the clearance of hepatotoxic bile
salts. CYP3A gene expression is induced by a large variety of xenobiotic compounds through SXR/PXR activation (Xie and Evans 2001). Confirmation that SXR and PXR act as xenobiotic receptors comes from mouse knockouts of PXR that abolish both CYP3A inducibility and the protection of liver from the effects of toxic compounds (Staudinger et al. 2001; Xie et al. 2000). Consistent with the lipid metabolic cascade model, two xenobiotic transporters, ABCB1 (or MDR1) and ABCC2 (or MRP2), are up-regulated in hepatocytes and intestinal cells by SXR activators and chemotherapeutic agents, such as Taxol (Dussault et al. 2001; Synold et al. 2001). Thus, this part of the regulatory circuit plays an important role in drug resistance. Taken together, the xenobiotic activation of CAR and SXR/PXR induces a positive feed-forward loop that aids in clearance of foreign chemicals and thereby resets the xenosensors for another round of signaling.