CAR

From LipidomicsWiki

CAR, THE XENOBIOTIC SENSOR

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).

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).

Taken together, the xenobiotic activation of CAR induces a positive feed-forward loop that aids in clearance of foreign chemicals and thereby resets the xenosensors for another round of signaling.