NAD(P)H:
Quinone Oxidoreductase1 (NQO1) also known as
DT-diaphorase is a
flavoprotein that catalyzes the two-electron reduction of
quinones,
quinone imines and
azo-dyes and thereby protects cells against mutagenicity and carcinogenicity resulting from
free radicals and toxic
oxygen metabolites generated by the one-electron reductions catalyzed by
cytochromes P450 and other
enzymes. High levels of NQO1 gene expression have been observed in liver, lung, colon and
breast tumors as compared to normal tissues of the same origin. The transcription of the NQO1 gene is activated in response to exposure to bifunctional (e.g.
beta-naphthoflavone (beta-NF), 2, 3, 7, 8 tetrachorodibenzo-
p-dioxin (
TCDD)) and monofunctional (phenolic
antioxidants/chemoprotectors e.g. 2(3)-tert-butyl-4-hydroxy-
anisole (
BHA)) inducers. The high level of expression of the NQO1 gene and its induction by beta-NF and
BHA require the presence of an AP1 binding site contained within the human Antioxidant Response Element (hARE) and are mediated by products of proto-oncogenes, Jun and Fos. Induction of NQO1 gene expression involves transfer of a redox signal from
xenobiotics to unknown 'redox
protein(s)' which in turn, modify the Jun and Fos
proteins for greater affinity towards the AP1 site of the NQO1 gene and activates transcription. The expression and regulation of the NQO1 gene is complex as many additional cis-elements have been identified in the promoter region and is a subject of great future interest. In addition to established
tumors, NQO1 gene expression is also increased in developing
tumors, indicating a role in cellular defense during
tumorigenesis. It has been proposed that low molecular weight
substance(s) can diffuse from
tumor cells into surrounding normal cells and activate the expression of the NQO1 gene. Purification and characterization of such
substance(s) may provide important information in regard to the mechanism of activation of NQO1 gene expression and the role of increased NQO1 expression in
tumor development. In view of the general consensus that NQO1 is over-expressed in
tumor cells and the realization that NQO1 may either activate or detoxify
xenobiotics, it is important to establish the role of NQO1 in the activation, and the detoxification of
xenobiotics and drugs and in the intrinsic sensitivity of
tumors to bioreductive alkylating aziridinyl
benzoquinones such as
diaziquone (
AZQ),
mitomycin C (MMC), and indoloquinone
EO9, as well as to the dinitrophenyl
aziridine,
CB1954, and the benzotriazine-di-N-
oxide,
SR 4233.