Regulation of genes encoding NAD(P)H:quinone oxidoreductases

doi:10.1016/S0891-5849(00)00306-3

Free Radical Biology and Medicine

Volume 29, Issues 3–4, August 2000, Pages 254-262

https://doi.org/10.1016/S0891-5849(00)00306-3 Get rights and content

Abstract

NAD(P)H:quinone oxidoreductase (NQO1) and NRH:quinone oxidoreductase (NQO2) are flavoproteins that catalyze two-electron reduction and detoxification of quinones and its derivatives. This leads to the protection of cells against redox cycling, oxidative stress, and neoplasia. NQO1 is expressed ubiquitously in all the tissues. However, the level of expression varied among the human tissues. NQO1 gene is expressed at higher levels in several tumor tissue types, including liver and colon, as compared to normal tissues of similar origin. NQO1 gene expression is coordinately induced with other detoxifying enzyme genes in response to xenobiotics, antioxidants, oxidants, heavy metals, and radiations. Deletion mutagenesis in the NQO1 gene promoter identified several cis-elements including antioxidant response element (ARE), a basal element, and AP-2 element. ARE elements have also been found in the promoter regions of other detoxifying enzyme genes including glutathione S-transferases. ARE is essentially required for expression and coordinated induction of NQO1 and other detoxifying enzyme genes. Nuclear transcription factors Nrf2 and c-Jun bind to the ARE and activate the gene expression. The binding of Nrf2 + c-Jun to the ARE required unknown cytosolic factor(s). In addition to Nrf2 and c-Jun, other nuclear transcription factors including Nrf1, Jun-B, and Jun-D also bind to the ARE and regulate expression and induction of NQO1 gene. A hypothetical model is presented based on the available information on ARE-mediated regulation of detoxifying enzyme genes. Briefly, the Nrf2 is retained in the cytosplasm by a repressor protein Keap1 in untreated normal cells. The treatment of cells with xenobiotics and antioxidants leads to the activation of unknown cytosolic factor(s) that catalyze modification of Nrf2 and/or Keap1. The modification follows dissociation of Nrf2 and Keap1. The free Nrf2 translocates in the nucleus. Nrf2 in the nucleus heterodimerizes with c-Jun and binds to the ARE resulting in the induction of NQO1 and other ARE-regulated genes expression. The identity of cytosolic factor(s) remains unknown.

Introduction

Quinones are widely distributed in nature and human exposure to them is extensive. Quinones of polycyclic aromatic hydrocarbons are abundant in all burnt organic materials, including automobile exhaust, cigarette smoke, and urban air particulates [reviewed in 1]. They are also found naturally in many foods, and compounds containing the quinoid nucleus are widely employed as antitumor agents. Quinones are highly reactive molecules and readily undergo either one- or two-electron reduction.

Section snippets

One-electron reduction and activation of quinones

One-electron reduction of quinones and its derivatives by enzymes such as cytochromes P450 (CYP 1A1 and CYP 1A2), cytochrome P450 reductase, ubiquinone oxidoreductase, xanthine oxidoreductase, and cytochrome b5 reductase, etc., generate unstable semiquinones that undergo redox cycling in the presence of molecular oxygen leading to the formation of highly reactive oxygen species, which cause electrophilic and oxidative stress, DNA damage, lipid peroxidation, membrane damage, cytotoxicity, and

Two-electron reduction and detoxification of quinones

The two-electron reduction and detoxification of quinones is catalyzed by NAD(P)H:quinone oxidoreductases [2]. Dr. Lars Ernster’s laboratory was the first to describe the presence of an oxidoreductase (diaphorase) enzyme activity in the rat liver cytosol that catalyzed reduction of 2,6-dichlorophenolindophenol [3]. This activity was interesting because it used NADH and NADPH both as electron donors with equal affinities. Dr. Ernster’s laboratory partially purified the enzyme and designated it

Expression and induction of NQO1 gene

NQO1 activity is ubiquitously present in all the tissues [37]. Several investigators have observed large variations in the NQO1 activity among different individuals, tissue types of the same individual, and between normal and tumor tissues [reviewed in 20]. It is generally accepted that tumor tissues and cells of hepatic and colon origin express higher levels of NQO1 gene as compared to normal tissues and cells of similar origins [reviewed in [2], [20]]. The normal tissues that surround the

Cis-elements and transacting factors that regulate the expression and induction of NQO1 gene

Deletion mutagenesis studies of the human NQO1 gene promoter identified several cis-elements that are essential for the expression and induction of the NQO1 gene (Fig. 2) [17], [53], [54]. One of these elements was 24 base pairs of the antioxidant response element (ARE) that are required for basal expression as well as induction of NQO1 gene in response to xenobiotics [β-naphthoflavone (β-NF)], antioxidants [2(3)-tert-butyl-4-hydroxy-anisole (BHA) and tert-butylhydroquinone (tBHQ)], and

Mechanism of signal transduction for ARE-mediated expression and induction of NQO1 gene

The various steps in the mechanism of signal transduction from antioxidants and xenobiotics to the Nrf1, Nrf2, Jun, and Fos proteins that bind to the ARE and regulate ARE-mediated basal expression and coordinated induction of the various detoxifying enzyme genes remains unknown. A hypothetical model showing ARE-mediated induction of NQO1 and other detoxifying enzyme genes expression in response to xenobiotics and antioxidants is shown (Fig. 3). Xenobiotics and antioxidants undergo metabolism

Acknowledgements

We thank our colleagues for helpful discussion. This investigation was supported by NIH grant GM47466.

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Regulation of genes encoding NAD(P)H:quinone oxidoreductases

Abstract

Introduction

Section snippets

One-electron reduction and activation of quinones

Two-electron reduction and detoxification of quinones

Expression and induction of NQO1 gene

Cis-elements and transacting factors that regulate the expression and induction of NQO1 gene

Mechanism of signal transduction for ARE-mediated expression and induction of NQO1 gene

Acknowledgements

Toxicol. Appl. Pharm.

Biochem. Biophys. Res. Commun.

Arch. Biochem. Biophys.

Arch. Biochem. Biophys.

Biochem. Biophys. Acta

J. Biol. Chem.

Arch. Biochem. Biophys.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Pharm.

Free Radic. Biol. Med.

Mutat. Res.

J. Biol. Chem.

J. Biol. Chem.

Arch. Biochem. Biophys.

J. Biol. Chem.

Biochem. Pharmacol.

Biochem. Pharmacol.

Trends Pharm

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Acta

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Cell

Gene expression of DT diaphorase (NQO1) in cancer cells

Soluble diaphorases in animal tissues

Acta Chem. Scand.

Human FAD-dependent NAD(P)H diaphorase

Biochem. J.

The human dioxin-inducible NAD(P)H:quinone oxidoreductase cDNA-encoded protein expressed in COS-1 cells is identical to diaphorase 4

Eur. J. Biochem.

Unexpected genetic and structural relationships of a long-forgotten flavoenzyme to NAD(P)H:quinone reductase (DT diaphorase)

Proc. Natl. Acad. Sci. USA

Human NAD(P)H:quinone oxidoreductase gene structure and induction by dioxin

Biochemistry