Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.5.2 (NQO1)
6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Flavonoids are present in fruits, vegetables and beverages derived from plants (tea, red wine), and in many dietary supplements or herbal remedies including Ginkgo Biloba, Soy Isoflavones, and Milk Thistle. Flavonoids have been described as health-promoting, disease-preventing dietary supplements, and have activity as cancer preventive agents. Additionally, they are extremely safe and associated with low toxicity, making them excellent candidates for chemopreventive agents. The cancer protective effects of flavonoids have been attributed to a wide variety of mechanisms, including modulating enzyme activities resulting in the decreased carcinogenicity of xenobiotics. This review focuses on the flavonoid effects on cytochrome P450 (CYP) enzymes involved in the activation of procarcinogens and phase II enzymes, largely responsible for the detoxification of carcinogens. A number of naturally occurring flavonoids have been shown to modulate the CYP450 system, including the induction of specific CYP isozymes, and the activation or inhibition of these enzymes. Some flavonoids alter CYPs through binding to the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, acting as either AhR agonists or antagonists. Inhibition of CYP enzymes, including CYP 1A1, 1A2, 2E1 and 3A4 by competitive or mechanism-based mechanisms also occurs. Flavones (chrysin, baicalein, and galangin), flavanones (naringenin) and isoflavones (genistein, biochanin A) inhibit the activity of aromatase (CYP19), thus decreasing estrogen biosynthesis and producing antiestrogenic effects, important in breast and prostate cancers. Activation of phase II detoxifying enzymes, such as UDP-glucuronyl transferase, glutathione S-transferase, and quinone reductase by flavonoids results in the detoxification of carcinogens and represents one mechanism of their anticarcinogenic effects. A number of flavonoids including fisetin, galangin, quercetin, kaempferol, and genistein represent potent non-competitive inhibitors of sulfotransferase 1A1 (or P-PST); this may represent an important mechanism for the chemoprevention of sulfation-induced carcinogenesis. Importantly, the effects of flavonoids on enzymes are generally dependent on the concentrations of flavonoids present, and the different flavonoids ingested. Due to the low oral bioavailability of many flavonoids, the concentrations achieved in vivo following dietary administration tend to be low, and may not reflect the concentrations tested under in vitro conditions; however, this may not be true following the ingestion of herbal preparations when much higher plasma concentrations may be obtained. Effects will also vary with the tissue distribution of enzymes, and with the species used in testing since differences between species in enzyme activities also can be substantial. Additionally, in humans, marked interindividual variability in drug-metabolizing enzymes occurs as a result of genetic and environmental factors. This variability in xenobiotic metabolizing enzymes and the effect of flavonoid ingestion on enzyme expression and activity can contribute to the varying susceptibility different individuals have to diseases such as cancer. As well, flavonoids may also interact with chemotherapeutic drugs used in cancer treatment through the induction or inhibition of their metabolism.
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PMID:Dietary flavonoids: effects on xenobiotic and carcinogen metabolism. 1628 44

The present study is an effort to identify a potent chemopreventive agent against various diseases (including cancer) in which oxidative stress plays an important causative role. Here, we investigated the effect of a hydroalcoholic (80% ethanol: 20% distilled water) extract of aerial roots of Tinospora cordifolia (50 and 100mg/kg body wt./day for 2 weeks) on carcinogen/drug metabolizing phase-I and phase-II enzymes, antioxidant enzymes, glutathione (GSH) content, lactate dehydrogenase and lipid peroxidation in liver of 8-week-old Swiss albino mice. The modulatory effect of the extract was also examined on extrahepatic organs, i.e., lung, kidney and forestomach, for the activities of GSH S-transferase (GST), DT-diaphorase (DTD), superoxide dismutase (SOD) and catalase. Significant increases in the levels of acid-soluble sulfhydryl (-SH) and cytochrome P(450) contents, and enzyme activities of cytochrome P(450) reductase, cytochrome b(5) reductase, GST, DTD, SOD, catalase, GSH peroxidase (GPX) and GSH reductase (GR) were observed in the liver. Both treated groups showed decreased malondialdehyde (MDA) formation. In lung SOD, catalase and GST; in kidney SOD and catalase; and in forestomach SOD, DTD and GST showed significant increase at both dose levels of treatment. BHA (0.75%, w/w in diet), a pure antioxidant compound, was used as a positive control. This group showed increase in hepatic levels of GSH content, cytochrome b(5), DTD, GST, GR and catalase, whereas MDA formation was inhibited significantly. In the BHA-treated group, the lung and kidney showed increased levels of catalase, DTD and GST, whereas SOD was significantly increased in the kidney and forestomach; the latter also showed an increase in the activities of DTD and GST. The enhanced GSH level and enzyme activities involved in xenobiotic metabolism and maintaining antioxidant status of cells are suggestive of a chemopreventive efficacy of T. cordifolia against chemotoxicity, including carcinogenicity, which warrants further investigation of active principle (s) present in the extract responsible for the observed effects employing various carcinogenesis models.
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PMID:Tinospora cordifolia induces enzymes of carcinogen/drug metabolism and antioxidant system, and inhibits lipid peroxidation in mice. 1636 Sep 36

Numerous experimental and epidemiological studies have demonstrated that polycyclic aromatic hydrocarbons (PAHs), which are major constituents of cigarette tobacco tar, are strongly involved in the pathogenesis of the cardiovascular diseases (CVDs). Knowing that PAH-induced toxicities are mediated by the activation of a cytosolic receptor, aryl hydrocarbon receptor (AhR), which regulates the expression of a group of xenobiotic metabolizing enzymes (XMEs) such as CYP1A1, CYP1A2, CYP1B1, NQO1, and GSTA1, suggests a direct link between AhR-regulated XMEs and CVDs. Therefore, identifying the localization and expression of the AhR and its regulated XMEs in the cardiovascular system (CVS) is of major importance in understanding their physiological and pathological roles. Generally, it was believed that the levels of AhR-regulated XMEs are lower in the CVS than in the liver; however, it has been shown that similar or even higher levels of expression are demonstrated in the CVS in a tissue- and species-specific manner. Moreover, most, if not all, AhR-regulated XMEs are differentially expressed in most of the CVS, particularly in the endothelium cells, aorta, coronary arteries, and ventricles. Although the exact mechanisms of PAH-mediated cardiotoxicity are not fully understood, several mechanisms are proposed. Generally, induction of CYP1A1, CYP1A2, and CYP1B1 is considered cardiotoxic through generating reactive oxygen species (ROS), DNA adducts, and endogenous arachidonic acid metabolites. However the cardioprotective properties of NQO1 and GSTA1 are mainly attributed to the antioxidant effect by decreasing ROS and increasing the levels of endogenous antioxidants. This review provides a clear understanding of the role of AhR and its regulated XMEs in the pathogenesis of CVDs, in which imbalance in the expression of cardioprotective and cardiotoxic XMEs is the main determinant of PAH-mediated cardiotoxicity.
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PMID:The role of aryl hydrocarbon receptor in the pathogenesis of cardiovascular diseases. 1687 60

Carbonyl groups are frequently found in endogenous or xenobiotic compounds. Reactive carbonyls, formed during lipid peroxidation or food processing, and xenobiotic quinones are able to covalently modify DNA or amino acids. They can also promote oxidative stress, the products of which are thought to be an important initiating factor in degenerative diseases or cancer. Carbonyl groups are reduced by an array of distinct NADPH-dependent enzymes, belonging to several oxidoreductase families. These reductases often show broad and overlapping substrate specificities and some well-characterized members, e.g., carbonyl reductase (CBR1) or NADPH-quinone reductase (NQO1) have protective roles toward xenobiotic carbonyls and quinones because metabolic reduction leads to less toxic products, which can be further metabolized and excreted. This review summarizes the current knowledge on structure and function relationships of the major human and mammalian carbonyl reductases identified.
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PMID:Carbonyl reductases: the complex relationships of mammalian carbonyl- and quinone-reducing enzymes and their role in physiology. 1700 25

The aryl hydrocarbon receptor (AhR) mediates a variety of biological responses to ubiquitous environmental pollutants. AhR together with ARNT, AhRR, HIF1alpha represent a novel basic helix-loop-helix/PAS family of transcriptional regulators. Their interplay may affect the xenobiotic response. In this study, the effect of i.p. administration of different AhR ligands on the expression of AhR, AhRR, ARNT, HIF1alpha and CYP1A1 and NAD(P)H: quinone oxidoreductase (NQO1), the enzymes controlled by AhR were examined in Sprague-Dawley rat liver. Quantitative real-time RT-PCR analysis revealed no changes in the mRNA expression of ARNT and HIF1alpha following 3-methylcholanthrene (3-MC), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or beta-naphthoflavone (BNF) treatment. AhRR expression was affected by TCDD but not by BNF and 3-MC. Expression of AhR mRNA and of the markers of its activation, CYP1A1 and NQO1, was significantly increased by administration of TCDD, 3-MC and, to lower extent, BNF. These results indicate that binding of the ligands to AhR up-regulates the mRNA transcription not only of CYP1A1 and NQO1, but also of AhR itself. The level of AhR induction depends on the potency of xenobiotic metabolizing enzymes inducer.
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PMID:The effect of aryl hydrocarbon receptor ligands on the expression of AhR, AhRR, ARNT, Hif1alpha, CYP1A1 and NQO1 genes in rat liver. 1706 94

Available data indicate that there are significant differences in individual susceptibility to lung cancer within the human population. It is believed to be underlie by inherited genetic predispositions related to the genetic polymorphism of several enzymes involved in the detoxification and xenobiotic metabolism. In this review, we collect and discuss the evidence reported up to date on the association between lung cancer and genetic polymorphism of cytochromes P450, N-acetyltransferase, glutathione S-transferases, microsomal epoxide hydrolase, NAD(P)H:quinone oxidoreductase, myeloperoxidase and glutathione peroxidase. All these genes might appear to be candidates for lung cancer susceptibility genes, nevertheless, the present state of the art still offers only a limited explanation of the link between such polymorphisms and increased risk of lung cancer.
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PMID:Polymorphism of selected enzymes involved in detoxification and biotransformation in relation to lung cancer. 1733 85

Phase II xenobiotic metabolizing enzymes confer amelioration of risk arising from potentially carcinogenic chemicals derived both endogenously, and exogenously, from food and the environment. In this study, efforts were made to isolate and identify potentially cancer preventive constituents from methanolic extracts of green onion (Allium cepa) directed by the quinone reductase (QR) induction bioassay using murine hepatoma (Hepa 1c1c7) cells. Crude methanolic extracts of green onion tissue were solvent-partitioned, and subsequently fractionated by flash chromatography, thin layer chromatography and high pressure preparative liquid chromatography to afford pure QR-inducing isolates. Multiple isolates were found active at inducing QR. One newly identified compound, 5-hydroxy-3-methyl-4-propylsulfanyl-5H-furan-2-one (3), and four known compounds: 5-(hydroxymethyl) furfural (1), acetovanillone (2), methyl 4-hydroxyl cinnamate (4) and ferulic acid methyl ester (5), were isolated and identified as active agents.
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PMID:Isolation and identification of potential cancer chemopreventive agents from methanolic extracts of green onion (Allium cepa). 1735 Jun 59

Benzo(a)pyrene (BaP) is a known human carcinogen and a suspected breast cancer complete carcinogen. BaP is metabolized by several metabolic pathways, some having bioactivation and others detoxification properties. BaP-quinones (BPQs) are formed via cytochrome P450 and peroxidase dependent pathways. Previous studies by our laboratory have shown that BPQs have significant growth promoting and anti-apoptotic activities in human MCF-10A mammary epithelial cells examined in vitro. Previous results suggest that BPQs act via redox-cycling and oxidative stress. However, because two specific BPQs (1,6-BPQ and 3,6-BPQ) differed in their ability to produce reactive oxygen species (ROS) and yet both had strong proliferative and EGF receptor activating activity, we utilized mRNA expression arrays and qRT-PCR to determine potential pathways and mechanisms of gene activation. The results of the present studies demonstrated that 1,6-BPQ and 3,6-BPQ activate dioxin response elements (DRE, also known as xenobiotic response elements, XRE) and anti-oxidant response elements (ARE, also known as electrophile response elements, EpRE). 3,6-BPQ had greater DRE activity than 1,6-BPQ, whereas the opposite was true for the activation of ARE. Both 3,6-BPQ and 1,6-BPQ induced oxidative stress-associated genes (HMOX1, GCLC, GCLM, and SLC7A11), phase 2 enzyme genes (NQO1, NQO2, ALDH3A1), PAH metabolizing genes (CYP1B1, EPHX1, AKR1C1), and certain EGF receptor-associated genes (EGFR, IER3, ING1, SQSTM1 and TRIM16). The results of these studies demonstrate that BPQs activate numerous pathways in human mammary epithelial cells associated with increased cell growth and survival that may play important roles in tumor promotion.
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PMID:Activation of dioxin response element (DRE)-associated genes by benzo(a)pyrene 3,6-quinone and benzo(a)pyrene 1,6-quinone in MCF-10A human mammary epithelial cells. 1746 51

Phase II detoxification enzymes are responsible for the detoxification and elimination of activated carcinogens, and thus act as important biomarkers for chemoprevention. In this study, we tested the chemopreventive activity of taxifolin, a flavanon compound purified from a mongolian medicinal plant, by measuring quinone reductase (QR) activity in HCT 116 cells. Taxifolin induced significant QR activity, but displayed relatively low cytotoxicity in cells (chemoprevention index=5.75). To identify the target genes regulated by taxifolin, DNA microarray was performed with a 3K human cancer chip containing 3096 human genes associated with carcinogenesis. Significant analysis of microarray (SAM) revealed 428 differentially expressed (DE) genes as statistically significant, with a false discovery rate (FDR) of 57.2% (delta=0.3366). Sixty-five genes, including a few detoxification enzymes (NQO1, GSTM1) and an antioxidant enzyme (TXNRD1), were up-regulated and 363 genes were down-regulated in the presence of 60 microM taxifolin. In view of the finding that selected genes of interest contained antioxidant response element (ARE), we hypothesize that taxifolin modulates chemopreventive genes through activation of the ARE. Transient transfection experiments using the ARE QR-CAT construct demonstrate that taxifolin significantly activates ARE, but not xenobiotic response element (XRE). In conclusion, taxifolin acts as a potential chemopreventive agent by regulating genes via an ARE-dependent mechanism.
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PMID:The chemopreventive effect of taxifolin is exerted through ARE-dependent gene regulation. 1754 Nov 56

This study investigated some aspects of xenobiotic metabolism in the Nototheniidae Trematomus bernacchii, a key sentinel species for monitoring Antarctic ecosystems. After laboratory exposure to beta-naphthoflavone (betaNF), basal levels and time-course induction of CYP1A, CYP1B and CYP3A were measured as enzymatic activities, immunoreactive protein content and mRNA expression in liver, gills, intestine and heart. Additional analyses in the liver included enzymatic activities of testosterone hydroxylase, (omega)- and (omega-1)-lauric acid hydroxylase and some phase II enzymes related to the AhR battery genes, DT-diaphorase, glutathione S-transferases and UDP-glucuronyl transferases. Responsiveness of hepatic CYP1A1 after exposure to betaNF demonstrated an higher sensitivity of MEROD than EROD activity and long lasting expression of mRNA still induced after 20 days from the treatment. Testosterone metabolism, oxidation of lauric acid and activities of phase II enzymes were not affected by betaNF indicating that their modulation is not mediated by Ah receptor. Induction of CYP1A was more limited in gills and absent in intestine and heart. The first nucleotide sequence for CYP1B1 in an Antarctic fish has been obtained, revealing a homology of 89% and 72% respectively to CYP1B1 of plaice and CYP1B2 of carp. Constitutive expression of CYP1B1 was restricted to gills where it was also induced by betaNF. Obtained results represent an additional contribution to the ecotoxicological characterization of T. bernacchii and further support the use of biomarkers for early detection of chemical pollution in Antarctica.
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PMID:Presence and inducibility by beta-naphthoflavone of CYP1A1, CYP1B1 and phase II enzymes in Trematomus bernacchii, an Antarctic fish. 1764 6


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