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CAR, Driving into the Future

Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709

Address all correspondence and requests for reprints to: Dr. Masahiko Negishi, Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709. E-mail: negishi{at}niehs.nih.gov.

The nuclear orphan receptor CAR is active in the absence of ligand with the unique capability to be further regulated by activators. A number of these activators, including phenobarbital, do not directly bind to the receptor. Considered a xenobiotic sensing receptor, CAR transcriptionally modifies the expression of genes involved in the metabolism and elimination of xenobiotics and steroids in response to these compounds and other cellular metabolites. Its hepatic expression pattern endows the liver with the ability to protect against not only exogenous but also endogenous insults. The mechanism of CAR activation is complex, involving translocation from the cytoplasm to the nucleus in the presence of activators, followed by further activation steps in the nucleus. Although this mechanism remains under investigation, we have summarized here the cellular signaling pathways elucidated so far and speculate on the mechanism by which CAR activators regulate gene expression through this network.

NURSA Molecule Pages Link:

Nuclear Receptors:   PXR  |  CAR  |  CAR-β  |  ERRγ  |  GR  |  NURR1  |  DHR38  |  LRH-1

Coregulators:   P/CAF  |  PGC-1  |  CBP  |  SRC-1  |  GRIP1  |  AIB1

Ligands:   CITCO  |  Phenobarbital  |  17β-Estradiol  |  Progesterone  |  Androstenol  |  TCPOBOP  |  Androstanol

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