Received for publication May 1, 2009.
Revised June 19, 2009.
Accepted for publication June 19, 2009.

The aldo-keto reductase Akr1b7 gene is a common transcriptional target of xenobiotic receptors PXR and CAR

Abstract

AKR1B7 (aldo-keto reductase family 1, member 7), a member of the AKR superfamily, has been suggested to play an important role in the detoxification of lipid peroxidation byproducts. The nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are xenosensors postulated to alleviate xeno- and endobiotic chemical insults. In this study, we show that the mouse Akr1b7 is a shared transcriptional target of PXR and CAR in the liver and intestine. Treatment of wild type mice with the PXR agonist pregnenolone-16-carbonitrile (PCN) activated Akr1b7 gene expression, whereas the effect was abrogated in PXR-/- mice. Similarly, the activation of Akr1b7 gene expression by the CAR agonist 1,4-bis[2-(3,5-dichlorpyridyloxyl)]-benzene (TCPOBOP), seen in wild type mice, was abolished in CAR^-/- mice. The promoter of Akr1b7 gene was activated by PXR and CAR, and this activation was achieved through the binding of PXR-RXR or CAR-RXR heterodimers to a DR-4 type nuclear receptor binding site found in the Akr1b7 gene promoter. At the functional level, treatment with PCN in wild type, but not PXR^-/-, mice, led to a decreased intestinal accumulation of malondialdehyde (MDA), a biomarker of lipid peroxidation. The regulation of Akr1b7 by PXR was independent of the liver X receptor (LXR), another nuclear receptor known to regulate this AKR isoform. Because a major function of Akr1b7 is to detoxify lipid peroxidation, the PXR-, CAR- and LXR-controlled regulatory network of Akr1b7 may have contributed to alleviate toxicity associated with lipid peroxidation.

Key words: Promoter analysis, Regulation - transcriptional, Regulation - xenobiotic