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Vol. 62, Issue 3, 638-646, September 2002
Nuclear Receptor Discovery Research (J.M.M., C.M.S., B.G., J.T.M.,
S.A.K.) and Bioscience Support (D.H.-B.), GlaxoSmithKline, Research
Triangle Park, North Carolina
The nuclear pregnane X receptor (PXR) and constitutive androstane
receptor (CAR) play central roles in protecting the body against
environmental chemicals (xenobiotics). PXR and CAR are activated by a
wide range of xenobiotics and regulate cytochrome P450 and other genes
whose products are involved in the detoxification of these chemicals.
In this report, we have used receptor-selective agonists together with
receptor-null mice to identify PXR and CAR target genes in the liver
and small intestine. Our results demonstrate that PXR and CAR regulate
overlapping but distinct sets of genes involved in all phases of
xenobiotic metabolism, including oxidative metabolism, conjugation, and
transport. Among the murine genes regulated by PXR were those encoding
PXR and CAR. We provide evidence that PXR regulates a similar program of genes involved in xenobiotic metabolism in human liver. Among the
genes regulated by PXR in primary human hepatocytes were the aryl
hydrocarbon receptor and its target genes CYP1A1 and
CYP1A2. These findings underscore the importance of
these two nuclear receptors in defending the body against a broad array
of potentially harmful xenobiotics.
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