Elsevier

Biochemical Pharmacology

Volume 58, Issue 10, 15 November 1999, Pages 1649-1655
Biochemical Pharmacology

Gene Expression and Developments
Antioxidant response element-mediated 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induction of human NAD(P)H:Quinone oxidoreductase 1 gene expression

https://doi.org/10.1016/S0006-2952(99)00245-2Get rights and content

Abstract

Antioxidant response element (ARE) is required for high basal expression of the human NAD(P)H:quinone oxidoreductase 1 (NQO1) gene in tumor cells and its induction in response to β-naphthoflavone and phenolic antioxidants. In this study, we have demonstrated that ARE also is required for induction of human NQO1 gene expression in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The various results suggest an alternate pathway for TCDD induction of human NQO1 gene expression. This pathway is independent of xenobiotic response element (XRE) and aromatic hydrocarbon (Ah) receptor. It is presumed that TCDD-induced expression of CYP1A1 leads to increased oxidative stress, resulting in transcriptional activation and/or modification of ARE-binding factors and increased expression of the human NQO1 gene.

Section snippets

Plasmids

The construction of pNQO1CAT1.55 has been described [3]. Plasmid pNQO1CAT1.55 contains 1.55 kb of the 5′ flanking region and 110 bp of the first exon from the human NQO1 gene. The plasmid pNQO1CAT1.55ΔARE was generated with selected primers and polymerase chain reaction (PCR). The human NQO1 gene promoter was amplified between −1550 and −472 and between −446 and +110 with selected primers and PCR to delete the region between −471 and −447 containing the ARE. The nucleotide sequences of the

Results and discussion

The toxic and mutagenic effects of TCDD are mediated by Ah receptor and XRE-mediated induction of expression of cytochrome P450 genes including the CYP1A1 gene 6, 7. The mechanism of induction of CYP1A1 gene expression by TCDD and Ah receptor is similar to that of members of the super family of steroid receptors 6, 7. It involves binding of TCDD to the Ah receptor, resulting in dissociation of Hsp90 from the Ah receptor and formation of a TCDD-Ah receptor complex. The Ah receptor-TCDD complex

Acknowledgements

This work was supported by NIH Grant GM 47466. We would like to thank Dr. Oliver Hankinson, University of California at Los Angeles, for providing us with the Hepa-1 mutant cell lines.

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    Then Nrf2 binds to antioxidant/electrophile-response elements (ARE) located in the regulatory regions of many defense enzyme genes to enhance cell survival (Giuliani et al., 2017; Suzuki and Yamamoto, 2015). Initially, Radjendirane and Jaiswal (1999) found that the inducer of AhR could induce the transcriptional expression of the phase II metabolic enzyme (NAD(P)H:quinoneoxidoreductase, NQO1) gene and analyzed the reasons for this phenomenon is the Nrf2-Keap1-AREs pathway could be directly or indirectly activated by TCDD and proposed whether there is an interaction between AhR-ARNT-XREs and Nrf2-Keap1-AREs signaling pathway. Therefore, the current interaction mechanism between AhR-ARNT-XREs and Nrf2-Keap1-AREs signaling pathway is inconclusive, especially whether there is an interaction function between AhR-ARNT-XREs and Nrf2-Keap1-AREs signaling pathway in molluscs and more in-depth studies are still needed in this topic.

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