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Review
. 2010 Sep 1;501(1):116-23.
doi: 10.1016/j.abb.2010.03.019. Epub 2010 Mar 31.

NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1), a multifunctional antioxidant enzyme and exceptionally versatile cytoprotector

Albena T Dinkova-Kostova  1 , Paul Talalay
Affiliations
Review

NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1), a multifunctional antioxidant enzyme and exceptionally versatile cytoprotector

Albena T Dinkova-Kostova et al. Arch Biochem Biophys. .

Abstract

NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1) is a widely-distributed FAD-dependent flavoprotein that promotes obligatory 2-electron reductions of quinones, quinoneimines, nitroaromatics, and azo dyes, at rates that are comparable with NADH or NADPH. These reductions depress quinone levels and thereby minimize opportunities for generation of reactive oxygen intermediates by redox cycling, and for depletion of intracellular thiol pools. NQO1 is a highly-inducible enzyme that is regulated by the Keap1/Nrf2/ARE pathway. Evidence for the importance of the antioxidant functions of NQO1 in combating oxidative stress is provided by demonstrations that induction of NQO1 levels or their depletion (knockout, or knockdown) are associated with decreased and increased susceptibilities to oxidative stress, respectively. Furthermore, benzene genotoxicity is markedly enhanced when NQO1 activity is compromised. Not surprisingly, human polymorphisms that suppress NQO1 activities are associated with increased predisposition to disease. Recent studies have uncovered protective roles for NQO1 that apparently are unrelated to its enzymatic activities. NQO1 binds to and thereby stabilizes the important tumor suppressor p53 against proteasomal degradation. Indeed, NQO1 appears to regulate the degradative fate of other proteins. These findings suggest that NQO1 may exercise a selective "gatekeeping" role in regulating the proteasomal degradation of specific proteins, thereby broadening the cytoprotective role of NQO1 far beyond its highly effective antioxidant functions.

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Figures

Figure 1
Figure 1. The multiple cytoprotective functions of NQO1
NQO1 catalyzes the obligatory 2-electron reduction of various exogenous and endogenous quinones, quinoneimines, nitroaromatic compounds and azo dyes. NQO1 has superoxide scavenging activity, which although much less efficient than superoxide dismutase (SOD), can be important in tissues or under conditions where expression of NQO1 is high and that of SOD is low. NQO1 stabilizes p53 and other tumor suppressor proteins which are otherwise degraded via the 20S proteasome. In Xenopus egg extracts, NQO1 stabilizes microtubules. It has been proposed that NQO1 can modulate the ratios of reduced/oxidized nicotinamide nucleotide pools.
Figure 2
Figure 2. The principle of the NQO1 bioassay
Murine Hepa1c1c7 cells are cultured in 96-well plates. Twenty-four hours later, cells are exposed to a range of concentrations of inducers for 48 hours. Then, cells are lysed and the activity of NQO1 is determined using menadione as a substrate and an NADPH-regenerating system. The menadiol reaction product reduces the tetrazolium yellow dye MTT to a purple formazan, the formation of which is quantitatively determined by its characteristic absorbance (in the range of 490 to 640 nm). The specific activity of NQO1 is plotted as a ratio of treated over control wells against the inducer concentration. CD value, the Concentration of an inducer that Doubles the enzyme activity. G6PDH, glucose-6-phosphate dehydrogenase.
Figure 3
Figure 3. The Keap1/Nrf2/ARE pathway
Under basal condition (dashed arrow), the dimeric multidomain protein Keap1 binds transcription factor Nrf2 via its Kelch domain and promotes the ubiquitination and proteasomal degradation of the transcription factor by functioning as an adaptor for Cul3-based E3 ligase. Inducers, all of which react with sulfhydryl groups, chemically modify specific highly reactive cysteine residues of Keap1 which then loses its ability to target Nrf2 for degradation. Consequently, Nrf2 is stabilized and becomes available for translocation (solid arrow) to the nucleus where it binds to AREs and triggers the expression of NQO1 and a battery of >100 other cytoprotective genes.
Figure 4
Figure 4. The antioxidant activity of NQO1
Mouse liver postmitochondrial supernatant fractions (S9) from untreated (containing 1.7 units of NQO1, uppermost trace) or BHA-treated (10.9 units NQO1, lowest trace) animals were incubated with menadione in the presence of NADPH-generating system, and the chemiluminescence due to formation of superoxide and singlet oxygen during the quinone redox cycling was recorded. The intermediate traces represent the chemiluminescence when liver fractions of untreated mice were used to which pure crystalline enzyme was added to produce 4.9, 5.5, or 10.9 units of NQO1. Note that the degree of suppression of the chemiluminescence was proportional to the amount of enzyme activity added, and was identical in fractions prepared from BHA-treated animals and those from control animals that had identical added levels of exogenous NQO1. [Reproduced with permission from H.J. Prochaska, P. Talalay, H. Sies. J. Biol. Chem. 262 (1987) 1931.]
Figure 5
Figure 5. The role of NQO1 in cellular protection against the toxicity of estrogen quinones
NQO1 catalyzes the obligatory 2-electron reduction of estrogen quinones to catechol estrogens which can then be conjugated and excreted. In doing so, NQO1 diverts the electrophilic quinones from participating in potentially deleterious processes that could lead to: (i) formation of depurinating mutagenic DNA adducts, (ii) sulfhydryl depletion, or (iii) one-electron reduction generating semiquinones and various reactive oxygen intermediates arising from redox cycling. In addition, the estrogen quinones themselves induce the gene expression of NQO1 and the synthesis of glutathione via the Keap1/Nrf2/ARE pathway. COMT, catechol O-methyl transferase; GSH/GST, glutathione/glutathione S-transferase; P450 R, cytochrome P450 reductase; SOD, superoxide dismutase. Adapted (with modifications) from Reference .
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