Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR.

Abstract:

:The cytochrome P450 (CYP) gene products such as CYP3A and CYP2B are essential for the metabolism of steroid hormones and xenochemicals including prescription drugs. Nuclear receptor SXR/PXR (steroid and xenobiotic receptor/pregnenolone X receptor) has been shown both biochemically and genetically to activate CYP3A genes, while similar studies have established constitutive androstane receptor (CAR) as a CYP2B regulator. The response elements in these genes are also distinct, furthering the concept of independent regulation. Unexpectedly, we found that SXR can regulate CYP2B, both in cultured cells and in transgenic mice via adaptive recognition of the phenobarbital response element (PBRE). In a type of functional symmetry, orphan receptor CAR was also found to activate CYP3A through previously defined SXR/PXR response elements. These observations not only provide a rational explanation for the activation of multiple CYP gene classes by certain xenobiotics, but also reveal the existence of a metabolic safety net that confers a second layer of protection to the harmful effects of toxic compounds and at the same time increases the propensity for drug-drug interactions.

journal_name

Genes Dev

journal_title

Genes & development

authors

Xie W,Barwick JL,Simon CM,Pierce AM,Safe S,Blumberg B,Guzelian PS,Evans RM

doi

10.1101/gad.846800

subject

Has Abstract

pub_date

2000-12-01 00:00:00

pages

3014-23

issue

23

eissn

0890-9369

issn

1549-5477

journal_volume

14

pub_type

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