NAD(P)H:Quinone oxidoreductase, (NQO1) is a flavoprotein which promotes obligatory two-electron reduction of quinones, preventing their participation in redox cycling, oxidative stress and neoplasia. High levels of NQO1 have been observed in several kinds of tumours including that of the liver, lung, colon and breast. Transcription of the NQO1 gene is increased in response to bifunctional [e.g. β-naphthoflavone (β-NF), 2,3,7,8,-tetrachlordibenzo-p-dioxin (dioxin)] and monofunctional [phenolic antioxidants/chemoprotectors e.g. 2(3)tert-butyl-4-hydroxy-anisole (BHA)] inducers. High basal expression of the NQO1 gene and its induction by β-NF and BHA are mediated by 31 bp of the antioxidant response element (ARE) containing more than one copy of the Aβ1/Aβ1-like binding sites, Jun and Fos and other(s) as yet unknown regulatory proteins. The arrangement of Aβ1 /Aβ1 -like elements within a short region of DNA may be important for β-NF and BHA response. The high basal expression of the NQO1 gene in several types of tumour tissues may be due to a high expression and/or modification of regulatory proteins that result from tumour formation. Signal transduction from β-NF and BHA for increased expression of the NQO1 gene involve metabolism of β-NF and generation of 'redox signals'. The sequence of events after generation of 'redox signals' leading to the modification/activation of regulatory proteins that bind to ARE and increase expression of the NQO1 gene are less clear. The possibilities include involvement of protein(s) which receive signals from β-NF and BHA and modulate the Jun and Fos proteins for increased binding to the ARE element or increased activities of the transcriptional activation domains of the regulatory proteins. The modifications in the regulatory proteins may be reduction of a cysteine residue in the DNA binding domain and/or phosphorylation of the DNA binding/transcriptional activation domains. Further studies are required to identify the intermediary components in the signal transduction pathway to completely understand the mechanism of induction of the NQO1 gene expression in response to β-NF and BHA.
Dioxin induction of the NQO1 gene expression is mediated by XRE, an element best characterized in the case of the CYP1A1 gene. As seen for the CYP1A1 gene, dioxin induction of NQO1 gene expression may involve binding of dioxin to the Ah receptor, release of the Hsp90 protein associated with the cytosolic Ah receptor, phosphorylation of Ah receptor by protein kinase C (PKC), heterodimerization with Arnt (phosphorylated by PKC?), nuclear translocation of dioxin-Ah, receptor-Arnt complex, binding at XRE element in the promoter region of the NQO1 gene resulting in activation of the NQO1 gene. The mechanism involving the Ah receptor and XRE may also be responsible in part for the β-NF induction of the NQO1 gene expression. This is because β-NF could bind to the Ah receptor, though at a much lower affinity as compared to dioxin. Similarly, it will be interesting to determine if dioxin induction of the NQO12 gene expression also involves the ARE element and Jun and Fos proteins. Indeed dioxin has been reported to increase the expression of the c-Fos gene. The regulation of the NQO1 gene is complex as several additional cis-elements have been identified in its promoter. Several other genes of phase II metabolism enzymes including glutathione-S-transferase, UDPG-transferase and perhaps epoxide hydrolase are expected to be co-ordinately regulated by mechanisms involving one or more ARE and XRE elements and Jun and Fos and Ah receptor proteins.