Roles of NAD(P)H:quinone Oxidoreductase 1 in Diverse Diseases.
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ABSTRACT:
SUBMITTER: Lee WS
PROVIDER: S-EPMC8703842 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposeNAD(P)H:Quinone Oxidoreductase 1 (NQO1) C609T missense variant (NQO1*2) and 29 basepair (bp)-insertion/deletion (I29/D) polymorphism of the NRH:Quinone Oxidoreductase 2 (NQO2) gene promoter have been proposed as predictive and prognostic factors for cancer development and progression. The purpose of this study is to investigate the relationship between NQO1/NQO2 genotype and clinico-pathological features of papillary thyroid microcarcinoma (PTMC).Materials and methodsGenomic DNA was isolated from 243 patients; and clinical data were retrospectively analyzed. NQO1*2 and tri-allelic polymorphism of NQO2 were investigated by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis.ResultsPTMC with NQO1*2 frequently exhibited extra-thyroidal extension as compared to PTMC with wild-type NQO1 (p=0.039). There was a significant relationship between I29/I29 homozygosity of NQO2 and lymph node metastasis (p=0.042). Multivariate analysis showed that the I29/I29 genotype was associated with an increased risk of lymph node metastasis (OR, 2.24; 95% CI, 1.10-4.56; p=0.026).ConclusionNQO1*2 and I29 allele of the NQO2 are associated with aggressive clinical phenotypes of PTMC, and the I29 allele represents a putative prognostic marker for PTMC.
| S-EPMC3743184 | biostudies-literature
Project description:The NAD(P)H:quinone acceptor oxidoreductase (NQO) gene family belongs to the flavoprotein clan and, in the human genome, consists of two genes (NQO1 and NQO2). These two genes encode cytosolic flavoenzymes that catalyse the beneficial two-electron reduction of quinones to hydroquinones. This reaction prevents the unwanted one-electron reduction of quinones by other quinone reductases; one-electron reduction results in the formation of reactive oxygen species, generated by redox cycling of semiquinones in the presence of molecular oxygen. Both the mammalian NQO1 and NQO2 genes are upregulated as a part of the oxidative stress response and are inexplicably overexpressed in particular types of tumours. A non-synonymous mutation in the NQO1 gene, leading to absence of enzyme activity, has been associated with an increased risk of myeloid leukaemia and other types of blood dyscrasia in workers exposed to benzene. NQO2 has a melatonin-binding site, which may explain the anti-oxidant role of melatonin. An ancient NQO3 subfamily exists in eubacteria and the authors suggest that there should be additional divisions of the NQO family to include the NQO4 subfamily in fungi and NQO5 subfamily in archaebacteria. Interestingly, no NQO genes could be identified in the worm, fly, sea squirt or plants; because these taxa carry quinone reductases capable of one- and two-electron reductions, there has been either convergent evolution or redundancy to account for the appearance of these enzyme functions whenever they have been needed during evolution.
| S-EPMC3500182 | biostudies-literature
Project description:Diabetic nephropathy (DN) is a major complication of diabetes mellitus. NAD(P)H:quinone oxidoreductase 1 (NQO1) is an antioxidant enzyme that has been involved in the progression of several kidney injuries. However, the roles of NQO1 in DN are still unclear. We investigated the effects of NQO1 deficiency in streptozotocin (STZ)-induced DN mice. NQO1 was upregulated in the glomerulus and podocytes under hyperglycemic conditions. NQO1 knockout (NKO) mice showed more severe changes in blood glucose and body weight than WT mice after STZ treatment. Furthermore, STZ-mediated pathological parameters including glomerular injury, blood urea nitrogen levels, and foot process width were more severe in NKO mice than WT mice. Importantly, urine albumin-to-creatinine ratio (ACR) was higher in healthy, non-treated NKO mice than WT mice. ACR response to STZ or LPS was dramatically increased in the urine of NKO mice compared to vehicle controls, while it maintained a normal range following treatment of WT mice. More importantly, we found that NQO1 can stimulate actin polymerization in an in vitro biochemical assay without directly the accumulation on F-actin. In summary, NQO1 has an important role against the development of DN pathogenesis and is a novel contributor in actin reorganization via stimulating actin polymerization.
| S-EPMC7576596 | biostudies-literature
Project description:NAD(P)H:quinone oxidoreductase type I (NQO1) is a target enzyme for triggered delivery of drugs at inflamed tissue and tumor sites, particularly those that challenge traditional therapies. Prodrugs, macromolecules, and molecular assemblies possessing trigger groups that can be cleaved by environmental stimuli are vehicles with the potential to yield active drug only at prescribed sites. Furthermore, quinone propionic acids (QPAs) covalently attached to prodrugs or liposome surfaces can be removed by application of a reductive trigger stimulus, such as that from NQO1; their rates of reductive activation should be tunable via QPA structure. We explored in detail the recombinant human NAD(P)H:quinone oxidoreductase type I (rhNQO1)-catalyzed NADH reduction of a family of substituted QPAs and obtained high precision kinetic parameters. It is found that small changes in QPA structure-in particular, single atom and function group substitutions on the quinone ring at R(1)-lead to significant impacts on the Michaelis constant (K(m)), maximum velocity (V(max)), catalytic constant (k(cat)), and catalytic efficiency (k(cat)/K(m)). Molecular docking simulations demonstrate that alterations in QPA structure result in large changes in QPA alignment and placement with respect to the flavin isoalloxazine ring in the active site of rhNQO1; a qualitative relationship exists between the kinetic parameters and the depth of QPA penetration into the rhNQO1 active site. From a quantitative perspective, a very good correlation is observed between log(k(cat)/K(m)) and the molecular-docking-derived distance between the flavin hydride donor site and quinone hydride acceptor site in the QPAs, an observation that is in agreement with developing theories. The comprehensive kinetic and molecular modeling knowledge obtained for the interaction of recombinant human NQO1 with the quinone propionic acid analogues provides insight into the design and implementation of the QPA trigger groups for drug delivery applications.
| S-EPMC3525107 | biostudies-literature
Project description:Ferroptosis, an emerging nonapoptotic, regulated cell death process distinguished by iron accumulation and subsequent lipid peroxidation, is intricately implicated in the development and progression of multiple cancer types. Here, we aimed to reveal that triggering ferroptosis is a promising treatment strategy for ovarian cancer. In this study, we not only validated that daphnetin caused ferroptosis, but evaluated the effects of daphnetin (and/or cisplatin) in vitro and vivo.Here, we elucidated that daphnetin, a natural product isolated from Daphne Korean Nakai, can exert antitumor effects by inducing the death and suppressing the migration of ovarian cancer cells. Subsequently, transcriptome analysis and ferroptosis inhibitor (Fer-1 and DFO) experiments revealed that there is a close correlation between daphnetin and ferroptosis in ovarian cancer. We further found that daphnetin induced ferroptosis in ovarian cancer cells, as evidenced by the accumulation of intracellular ferrous iron (Fe2+), reactive oxygen species (ROS) and lipid peroxides, as well as the depletion of glutathione (GSH) and ferroptosis indicators (SLC7A11 and GPX4). In particular, daphnetin effectively reduced the mRNA and protein levels of NQO1 (a ubiquitous flavoenzyme), and a high expression level of NQO1 was significantly associated with poor prognosis and ferroptosis resistance in ovarian cancer patients. Furthermore, NQO1 activation markedly attenuated daphnetin-induced cell death, migration and ferroptotic events in vitro and vivo. Interestingly, we also found that treatment with daphnetin, a negative regulator of NQO1, in combination with cisplatin synergistically induced ovarian cancer cell cytotoxicity. This study demonstrated that daphnetin induces ferroptosis by inhibiting NQO1 in ovarian cancer cells. Our findings identified NQO1 as a new daphnetin target and suggested that targeting NQO1 might have therapeutic effects on ovarian cancer.
2024-05-23 | GSE267812 | GEO
Project description:NAD(P)H: quinone oxidoreductase 1 (NQO1) is a ubiquitous flavoenzyme that catalyzes two-electron reduction of various quinones by utilizing NAD(P)H as an electron donor. Our previous study found that progesterone (PG) can protect cardiomyocytes from apoptosis induced by doxorubicin (Dox). Microarray analyses of genes induced by PG had led to the discovery of induction of NQO1 mRNA. We report here that PG induces NQO1 protein and its activity in a dose-dependent manner. Whereas NQO1 is well known as a target gene of Nrf2 transcription factor due to the presence of antioxidant response element (ARE) in the promoter, PG did not activate the ARE, suggesting Nrf2-independent induction of NQO1. To address the role of NQO1 induction in PG-induced cytoprotection, we tested the effect of NQO1 inducer ?-naphthoflavone and inhibitor dicoumarol. Induction of NQO1 by ?-naphthoflavone decreased Dox-induced apoptosis and potentiated the protective effect of PG as measured by caspase-3 activity. PG-induced NQO1 activity was inhibited with dicoumarol, which did not affect PG-induced cytoprotection. Dicoumarol treatment alone potentiated Dox-induced caspase-3 activity. These data suggest that while NQO1 plays a role in PG-induced cytoprotection, there are additional components contributing to PG-induced cytoprotection.
| S-EPMC4128173 | biostudies-literature
Project description:Soluble quinone oxidoreductases catalyze transfer of
| S-EPMC9330140 | biostudies-literature
Project description:The Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response elements pathway enables cells to survive oxidative stress conditions through regulating the expression of cytoprotective enzymes such asquinone oxidoreductase 1 (NQO1). This work presents the design and synthesis of novel anilinoquinazoline derivatives (2-16a) and evaluation of their NQO1 inducer activity in murine cells. Molecular docking of the new compounds was performed to assess their ability to inhibit Keap1-Nrf2 protein-protein interaction through occupying the Keap1-Nrf2-binding domain, which leads to Nrf2 accumulation and enhanced gene expression of NQO1. Docking results showed that all compounds can potentially interact with Keap1; however, 1,5-dimethyl-2-phenyl-4-(2-phenylquinazolin-4-ylamino)-1,2-dihydropyrazol-3-one (9), the most potent inducer, showed the largest number of interactions with key amino acids in the binding pocket (Arg483, Tyr525, and Phe478) compared to the native ligand or any other compound in this series.
| S-EPMC4982500 | biostudies-literature
Project description:Detoxicating enzymes NAD(P)H:quinone oxidoreductase 1 (NQO1) and NRH:quinone oxidoreductase 2 (NQO2) catalyze the two-electron reduction of quinone-like compounds. The protective role of the polymorphic NQO1 and NQO2 enzymes is especially of interest in the liver as the major site of drug bioactivation to chemically reactive drug metabolites. In the current study, we quantified the concentrations of NQO1 and NQO2 in 20 human liver donors and NQO1 and NQO2 activities with quinone-like drug metabolites. Hepatic NQO1 concentrations ranged from 8 to 213 nM. Using recombinant NQO1, we showed that low nM concentrations of NQO1 are sufficient to reduce synthetic amodiaquine and carbamazepine quinone-like metabolites in vitro. Hepatic NQO2 concentrations ranged from 2 to 31 ?M. NQO2 catalyzed the reduction of quinone-like metabolites derived from acetaminophen, clozapine, 4'-hydroxydiclofenac, mefenamic acid, amodiaquine, and carbamazepine. The reduction of the clozapine nitrenium ion supports association studies showing that NQO2 is a genetic risk factor for clozapine-induced agranulocytosis. The 5-hydroxydiclofenac quinone imine, which was previously shown to be reduced by NQO1, was not reduced by NQO2. Tacrine was identified as a potent NQO2 inhibitor and was applied to further confirm the catalytic activity of NQO2 in these assays. While the in vivo relevance of NQO2-catalyzed reduction of quinone-like metabolites remains to be established by identification of the physiologically relevant co-substrates, our results suggest an additional protective role of the NQO2 protein by non-enzymatic scavenging of quinone-like metabolites. Hepatic NQO1 activity in detoxication of quinone-like metabolites becomes especially important when other detoxication pathways are exhausted and NQO1 levels are induced.
| S-EPMC5997408 | biostudies-literature
Project description:Painful bladder syndrome (PBS), or interstitial cystitis, is a poorly understood chronic disease that is characterized by thinning of the bladder epithelium and intense pain. Here we demonstrate that NAD(P)H:quinone oxidoreductase 1(-/-) (NQO1(-/-)) mice developed in our laboratory represent a new animal model of PBS. NQO1 is known to protect against physiological stress as well as protecting transcription factors against proteasomal degradation. In this study we demonstrate that NQO1 is necessary for bladder epithelium integrity and to prevent the development/progression of PBS. We observed downregulation of energy metabolism, adhesion, and apoptotic signaling cascades, which led to mitochondrial aberrations and profound alterations in energy metabolism, increased susceptibility to reactive oxygen species generation, and apoptosis in luminal epithelium in NQO1(-/-) mice that were absent in wild-type mice. These pathophysiological changes led to the incidence of PBS in NQO1(-/-) mice. Altogether, the results demonstrate for the first time that NQO1 is an endogenous factor in protection against PBS.
| S-EPMC3495563 | biostudies-literature