DT-diaphorase as a quinone reductase: A cellular control device against semiquinone and superoxide radical formation

Lind, Christina; Hochstein, Paul; Ernster, Lars

doi:10.1016/0003-9861(82)90202-8

Cited by 491 publications

(154 citation statements)

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“…Firstly, the quinones are mutagenic compounds and, secondly, the mutagenicity of BP is not only caused by BPDE but also by BP-3,6-Q. The various results also support the proposed chemopreventive role for NQO1 (Lind et al, 1982;Chesis et al, 1984;O'Brien, 1991;Monks et al, 1992;Joseph and Jaiswal, 1994;Talalay et al, 1995) (Figure 4). However, a careful analysis of the mutation spectra induced by metabolites of BP-3,6-Q generated by NQOI suggests that further studies are required to attribute an exclusive chemoprevention role for NQO1.…”

Section: Discussionsupporting

confidence: 52%

NAD(P)H:quinone oxidoreductase 1 reduces the mutagenicity of DNA caused by NADPH:P450 reductase-activated metabolites of benzo(a)pyrene quinones

Joseph

Jaiswal²

1998

Br J Cancer

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Summary The role of microsomal NADPH:cytochrome P450 reductase (P450 reductase) and cytosolic NAD(P)H:quinone oxidoreductase 1 (NQO1 or DT-diaphorase) in the mutagenicity of benzo(a)pyrene-3,6-quinone (BP-3,6-Q) was studied using supF tRNA gene as the mutational target. pUB3 carrying the supF tRNA gene upon transformation into the Escherichia coli ES87 cells exhibited a spontaneous mutation frequency of 0.62 x 10-6. Chemical modification of the pUB3 DNA with BP-3,6-Q caused a fourfold increase in the mutation frequency, compared with the spontaneous mutations. P450 reductase catalysed metabolic activation of BP-3,6-Q into reactive products (semiquinone and reactive oxygen species), which caused a further increase in the mutation frequency to eighffold over spontaneous mutations. Oxygen radical scavengers (SOD and catalase) blocked the P450 reductase-activated BP-3,6-Q-induced stimulation of mutations. This indicates that redox cycling of the semiquinone leading to the generation of reactive oxygen species (ROS) was directly responsible for the increased mutation frequency of P450 reductase-activated BP-3,6-Q. Analysis of the mutation spectra revealed that P450 reductaseactivated BP-3,6-Q showed a significantly higher preference for frameshift mutations, particularly deletions, compared with the spontaneous mutations and the mutations generated by benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE). The single most frequently observed mutation by P450 reductase-activated quinone (semiquinone + ROS) was deletion of a single guanosine. Among the base substitutions, G:C -> T:A, G:C -+ A:T and G:C --C:G were also noticed. Interestingly, NQO1 competed with P450 reductase and specifically prevented the P450 reductase-activated BP-3,6-Q-induced mutations. However, BP-hydroquinone (BP-3,6-HQ) generated during the metabolic reduction of BP-3,6-Q catalysed by NQO1 caused specific mutations involving the deletion of a single cytosine from the DNA sequence 5'-CCCCC-3' in supF tRNA gene at a significantly high frequency. A similar cytosine deletion was also observed with benzoquinone hydroquinone (HQ), indicating that the deletion of cytosine is associated with a hydroquinone class of compounds. These results suggest that: (1) quinones and P450 reductase-activated products of quinones (semiquinones and ROS) are mutagenic compounds; (2) the mutational spectra of quinones, semiquinones and hydroquinones differ from each other with respect to their mutational frequency and specificity; (3) NQO1 competes with P450 reductase and protects the cells from quinone mutagenicity; and (4) the NQO1 -metabolized quinones (hydroquinones), if not eliminated, cause specific mutations that are not observed with quinones and P450 reductase-activated quinones (semiquinones and ROS).Keywords: NAD(P)H:quinone oxidoreductase 1; P450 reductase; benzo(a)pyrene-3,6-quinone; mutagenicityThe aetiology of human cancer is quite diverse and exposure to chemical carcinogens, particularly those present in the environment [e.g. benzo(a)pyrene (BP)] as contamin...

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Section: Discussionsupporting

confidence: 52%

NAD(P)H:quinone oxidoreductase 1 reduces the mutagenicity of DNA caused by NADPH:P450 reductase-activated metabolites of benzo(a)pyrene quinones

Joseph

Jaiswal²

1998

Br J Cancer

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“…NQO1, or DT-diaphorase, is a flavin-containing quinone reductase with a broad substrate specificity. 6 NQO1 catalyzes the reduction in various quinones through a two-electron reduction mechanism using either NADH or NADPH as a reducing cofactor, and it is inhibited by the competitive inhibitor dicoumarol. 7 This two-electron reduction prevents the formation of free radicals (semiquinones) and highly reactive oxygen species (ROS), thus protecting cells against quinones and their derivatives that are by large carcinogens.…”

Section: Ubiquitin-independent P53 Proteasomal Degradationmentioning

confidence: 99%

Ubiquitin-independent p53 proteasomal degradation

2009

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The mechanism of p53 proteasomal degradation through polyubiquitination is well characterized. The basic assumption behind this mechanism is that p53 is inherently stable unless sensitized to degradation by polyubiquitination. However, a number of studies provide evidence for p53 to be naturally unstable. Consistent with this attribute is the fact that both p53 N-and C-termini are intrinsically unstructured. Recent findings provide evidence for p53 to be degraded by the 20S proteasome by default unless it escapes this process. A number of mechanisms were demonstrated and proposed to play a role in rescuing p53 from default degradation. These mechanisms, their biological implications, and relevance to cancer are reviewed in this article.

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“…This prodrug is the prototype bioreductive alkylating agent and its activation involves the reduction of the quinone group leading to interstrand DNA crosslink formation and cell death (Sartorelli 1986;Workman and Stratford 1993). A major pathway resulting in MMC activation is catalyzed by the enzyme DT-diaphorase (NAD(P)H:quinone oxidoreductase 1; NQO1; DTD), a cytosolic two-electron reductase ubiquitously expressed (Siegel et al 1990;Ross et al 1993Ross et al ,1994Workman 1994) that is known to catalyze the biotransformation of many xenobiotics, including some that are carcinogens (phase II detoxification processes) and some that are antineoplastic agents (bioactivation processes) (Lind et al 1982;Chesis et al 1984). However, a second pathway catalyzed by the one-electron NADPH-dependent cytochrome P450 reductase has been described in individuals with no DTD activity because of a point mutation in the NQO1 gene, leading to minor antitumor efficacy and to the production of toxic semiquinone intermediates (Plumb and Workman 1994;Niedermeyer et al 1999).…”

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confidence: 99%

NAD(P)H:Quinone Oxidoreductase 1 Expression in Kidney Podocytes

Zappa

Ward

Pedrinis

et al. 2003

J Histochem Cytochem.

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(FZ,TW,JB,AM), and Institute of Pathology of Southern Switzerland, Locarno, Switzerland (EP) S U M M A R Y NAD(P)H:quinone oxidoreductase 1 (NQO1; DT-diaphorase; DTD) is a cytosolic two-electron reductase, and compounds of the quinone family such as mitomycin C are efficiently bioactivated by this enzyme. The observation that DT-diaphorase is highly expressed in many cancerous tissues compared to normal tissues has provided us with a potentially selective target that can be exploited in the design of novel anticancer agents. Because of the relative lack of information about the cell-specific expression of DT-diaphorase, the purpose of this study was to map the distribution of this enzyme in normal human tissues. Fifteen tissue samples from normal human kidney were analyzed for expression of DT-diaphorase by immunohistochemistry (two-step indirect method). We found a specific high expression of DT-diaphorase in glomerular visceral epithelial cells (podocytes). These results suggest that a high expression of DT-diaphorase in podocytes could play a major role in the pathogenesis of renal toxicity and mitomycin C-induced hemolytic uremic syndrome, in which injury to the glomerular filtration mechanism is the primary damage, leading to a cascade of deleterious events including microangiopathic hemolytic anemia and thrombocytopenia. This observation has potential therapeutic implications because the DT-diaphorase metabolic pathway is influenced by many agents, including drugs, diet, and environmental cell factors such as pH and oxygen tension.

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DT-diaphorase as a quinone reductase: A cellular control device against semiquinone and superoxide radical formation

Cited by 491 publications

References 16 publications

NAD(P)H:quinone oxidoreductase 1 reduces the mutagenicity of DNA caused by NADPH:P450 reductase-activated metabolites of benzo(a)pyrene quinones

NAD(P)H:quinone oxidoreductase 1 reduces the mutagenicity of DNA caused by NADPH:P450 reductase-activated metabolites of benzo(a)pyrene quinones

Ubiquitin-independent p53 proteasomal degradation

NAD(P)H:Quinone Oxidoreductase 1 Expression in Kidney Podocytes

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