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The role of the dioxin-responsive element cluster between the Cyp1a1 and Cyp1a2 loci in aryl hydrocarbon receptor biology

Nukaya, Manabu, Moran, Susan, Bradfield, Christopher A.·2009·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0809613106
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Abstract

The aryl hydrocarbon receptor (AHR) plays a central role in 2,3,7,8-tetrachlorodibenzo- p -dioxin (dioxin) hepatotoxicity, regulation of xenobiotic metabolism, and hepatovascular development. Each of these processes appears to be dependent on binding of the AHR to dioxin- responsive elements (DREs) within the genome. The Cyp1a1 and Cyp1a2 loci represent linked genes thought to play important roles in AHR biology. In the mouse, 8 DREs are located in the 14-kb intergenic region between the Cyp1a1 and Cyp1a2 genes. Seven of these DREs, collectively known as the DRE cluster (DREC), are located 1.4 kb upstream of the Cyp1a1 transcriptional start site and 12.6 kb upstream of the Cyp1a2 start site. To investigate the role of the DREC in each aspect of AHR biology, we generated a DREC-deficient mouse model through homologous recombination. Using this mouse model, we demonstrate that the DREC controls the adaptive up-regulation of both Cyp1a1 and Cyp1a2 genes in vivo. Using selected aspects of acute hepatic injury as endpoints, we also demonstrate that DREC null mice are more sensitive to dioxin-induced hepatotoxicity than WT mice. The results of parallel toxicologic studies using individual Cyp1a1 and Cyp1a2 null mice support the observation that up-regulation of these P450s is not the cause of many aspects of dioxin hepatotoxicity. Finally, we observed normal closure of the ductus venosus (DV) in DREC null mice. Given the 100% penetrance of patent DV in Ahr null mice, these results indicate that Cyp1a1 and Cyp1a2 do not play a dominant role in AHR-mediated vascular development.

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Metadata

Authors
Nukaya, M., Moran, S., & Bradfield, C. A.
Affiliations
McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2009-03-24
Volume
106
Issue
12
Pages
4923-4928
ISSN
  • 0027-8424
  • 1091-6490
DOI
10.1073/pnas.0809613106
Cited by
91
References
5
Language
en

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CoChat. (2026). Citation check: The role of the dioxin-responsive element cluster between the Cyp1a1 and Cyp1a2 loci in aryl hydrocarbon receptor biology. https://app.cochat.ai/papers/10.1073/pnas.0809613106
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Nukaya, M., Moran, S., & Bradfield, C. A. (2009). The role of the dioxin-responsive element cluster between the Cyp1a1 and Cyp1a2 loci in aryl hydrocarbon receptor biology. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.0809613106