Molecular Pharmacology of NRH:Quinone Oxidoreductase 2: A Detoxifying Enzyme Acting as an Undercover Toxifying Enzyme

Janda, Elżbieta; Nepveu, Françoise; Calamini, Barbara; Ferry, Gilles; Boutin, Jean A.

doi:10.1124/molpharm.120.000105

Cited by 27 publications

(29 citation statements)

References 121 publications

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“…Among these targets, NQO2, also known as QR2 (quinone oxidoreductase 2), appears well characterized in a series of crystallographic studies, yet very few papers convincingly show that the physical interaction with flavonoids or other polyphenols causes a specific biological function [ 26 ]. NQO2 binds to and is inhibited by resveratrol by a direct physical interaction [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

“…NQO2 is a cytoplasmic flavoenzyme catalyzing two-electron reductions of endo- and xenobiotic quinones. Similar to other Phase I and II drug metabolizing enzymes, it is regulated by Nrf2 and other transcription factors that bind to antioxidant response elements (ARE) present in the NQO2 promoter region [ 26 , 30 ]. The most peculiar feature of NQO2 is its inability to recognize NADH, but N-alkyl nicotinamide derivatives as its co-substrates, in contrast to its next of a kind, NADH: quinone oxidoreductase 1 (NQO1).…”

Section: Introductionmentioning

confidence: 99%

“…The most peculiar feature of NQO2 is its inability to recognize NADH, but N-alkyl nicotinamide derivatives as its co-substrates, in contrast to its next of a kind, NADH: quinone oxidoreductase 1 (NQO1). NQO2 is highly expressed in liver and kidney, where it may play both a detoxifying as well as a toxifying function, depending on the substrate [ 26 ]. In this regard, NQO2 has been shown to mediate the toxic effect of certain quinones mainly in ortho conformation as well as other non-quinonic compounds, such as parkinsonian toxins, the antitumor drugs CB154 and mitomycin [ 26 , 31 , 32 ].…”

Section: Introductionmentioning

confidence: 99%

“…NQO2 is highly expressed in liver and kidney, where it may play both a detoxifying as well as a toxifying function, depending on the substrate [ 26 ]. In this regard, NQO2 has been shown to mediate the toxic effect of certain quinones mainly in ortho conformation as well as other non-quinonic compounds, such as parkinsonian toxins, the antitumor drugs CB154 and mitomycin [ 26 , 31 , 32 ]. The biological roles of NQO2 may involve other processes beside the reduction of quinones and drug metabolism, such as the regulation of oxidative stress and cell death [ 32 ], protein stability [ 33 ], inflammation, and memory formation in the cortex [ 34 , 35 ], but some of these findings need further consolidation.…”

Section: Introductionmentioning

confidence: 99%

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Apigenin and Luteolin Regulate Autophagy by Targeting NRH-Quinone Oxidoreductase 2 in Liver Cells

et al. 2021

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Dietary flavonoids stimulate autophagy and prevent liver dysfunction, but the upstream signaling pathways triggered by these compounds are not well understood. Certain polyphenols bind directly to NRH-quinone oxidoreductase 2 (NQO2) and inhibit its activity. NQO2 is highly expressed in the liver, where it participates in quinone metabolism, but recent evidence indicates that it may also play a role in the regulation of oxidative stress and autophagy. Here, we addressed a potential role of NQO2 in autophagy induction by flavonoids. The pro-autophagic activity of seven flavonoid aglycons correlated perfectly with their ability to inhibit NQO2 activity, and flavones such as apigenin and luteolin showed the strongest activity in all assays. The silencing of NQO2 strongly reduced flavone-induced autophagic flux, although it increased basal LC3-II levels in HepG2 cells. Both flavones induced AMP kinase (AMPK) activation, while its reduction by AMPK beta (PRKAB1) silencing inhibited flavone-induced autophagy. Interestingly, the depletion of NQO2 levels by siRNA increased the basal AMPK phosphorylation but abrogated its further increase by apigenin. Thus, NQO2 contributes to the negative regulation of AMPK activity and autophagy, while its targeting by flavones releases pro-autophagic signals. These findings imply that NQO2 works as a flavone receptor mediating autophagy and may contribute to other hepatic effects of flavonoids.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Apigenin and Luteolin Regulate Autophagy by Targeting NRH-Quinone Oxidoreductase 2 in Liver Cells

et al. 2021

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“…This result was further confirmed by the detection of the glucuronide form of menadiol. In a more general context, after having pointed out the ambiguous role of NQO2 as a detoxifying enzyme (Boutin et al, 2019;Janda et al, 2020), we present data clearly showing that in more relevant conditions, for example in the presence of the conjugating enzyme(s), NQO2 would recuperate its detoxifying role, in line with the NQO1 one. In this pathway, NQO2 acts as a drug metabolizing Phase I enzyme, leading to an 'activated' molecule that can be conjugated by Phase II enzymes of the next step of drug metabolizing machinery.…”

Section: Discussionmentioning

confidence: 62%

Association of NQO2 With UDP-Glucuronosyltransferases Reduces Menadione Toxicity in Neuroblastoma Cells

Chhour

Pério

Gayon³

et al. 2021

Front. Pharmacol.

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The balance between detoxification and toxicity is linked to enzymes of the drug metabolism Phase I (cytochrome P450 or oxidoreductases) and phase II conjugating enzymes (such as the UGTs). After the reduction of quinones, the product of the reaction, the quinols—if not conjugated—re-oxidizes spontaneously to form the substrate quinone with the concomitant production of the toxic reactive oxygen species (ROS). Herein, we documented the modulation of the toxicity of the quinone menadione on a genetically modified neuroblastoma model cell line that expresses both the quinone oxidoreductase 2 (NQO2, E.C. 1.10.5.1) alone or together with the conjugation enzyme UDP-glucuronosyltransferase (UGT1A6, E.C. 2.4.1.17), one of the two UGT isoenzymes capable to conjugate menadione. As previously shown, NQO2 enzymatic activity is concomitant to massive ROS production, as previously shown. The quantification of ROS produced by the menadione metabolism was probed by electron-paramagnetic resonance (EPR) on cell homogenates, while the production of superoxide was measured by liquid chromatography coupled to mass spectrometry (LC-MS) on intact cells. In addition, the dysregulation of the redox homeostasis upon the cell exposure to menadione was studied by fluorescence measurements. Both EPR and LCMS studies confirmed a significant increase in the ROS production in the NQO2 overexpressing cells due to the fast reduction of quinone into quinol that can re-oxidize to form superoxide radicals. However, the effect of NQO2 inhibition was drastically different between cells overexpressing only NQO2 vs. both NQO2 and UGT. Whereas NQO2 inhibition decreases the amount of superoxide in the first case by decreasing the amount of quinol formed, it increased the toxicity of menadione in the cells co-expressing both enzymes. Moreover, for the cells co-expressing QR2 and UGT the homeostasis dysregulation was lower in presence of menadione than for the its counterpart expressing only QR2. Those results confirmed that the cooperation of the two enzymes plays a fundamental role during the cells’ detoxification process. The fluorescence measurements of the variation of redox homeostasis of each cell line and the detection of a glucuronide form of menadiol in the cells co-expressing NQO2 and UGT1A6 enzymes further confirmed our findings.

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Homeostatic Shrinkage of Dendritic Spines Requires Melatonin Type 3 Receptor Activation During Sleep

Li,

et al. 2024

Advanced Science

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High‐frequency oscillatory activity in cognition‐related neural circuits during wakefulness consistently induces the growth of dendritic spines and axonal terminals. Although these structural changes are essential for cognitive functions, it is hypothesized that if these newly expanded structures fail to establish functional connections, they may become superfluous. Sleep is believed to facilitate the reduction of such redundant structures to maintain neural homeostasis. However, the mechanisms underlying this pruning process during sleep remain poorly understood. In this study, that melatonin type 3 receptors (MT3Rs) are selectively expressed in the stellate neurons of the medial entorhinal cortex (MEC) is demonstrated, an area where high melatonin levels are detected during sleep. Activation of MT3Rs during sleep initiates the shrinkage of dendritic spines in stellate neurons by downregulating neural network activity and dephosphorylating synaptic proteins in the MEC. This process is disrupted when MT3R expression is knocked down or when MT3Rs are blocked during sleep. Notably, interference with MT3Rs in the MEC during sleep impairs the acquisition of spatial memory but does not affect object memory acquisition following sleep. These findings reveal novel molecular mechanisms involving melatonin and MT3Rs in the regulation of dendritic spine shrinkage during sleep, which is crucial for the acquisition and consolidation of spatial memory.

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Molecular Pharmacology of NRH:Quinone Oxidoreductase 2: A Detoxifying Enzyme Acting as an Undercover Toxifying Enzyme

Cited by 27 publications

References 121 publications

Apigenin and Luteolin Regulate Autophagy by Targeting NRH-Quinone Oxidoreductase 2 in Liver Cells

Apigenin and Luteolin Regulate Autophagy by Targeting NRH-Quinone Oxidoreductase 2 in Liver Cells

Association of NQO2 With UDP-Glucuronosyltransferases Reduces Menadione Toxicity in Neuroblastoma Cells

Homeostatic Shrinkage of Dendritic Spines Requires Melatonin Type 3 Receptor Activation During Sleep

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