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)

The naphthoquinone moiety was proven to be essential to the biological activities of sakyomicin A using various naphthoquinone derivatives. Among the naphthoquinones tested, juglone (5-hydroxy-1,4-naphthoquinone) which resembles the partial structure of sakyomicin A was the most active in cytotoxicity against murine lymphosarcoma L5178Y cells, electron acceptor function in the oxidation of NADH by Clostridium kluyveri diaphorase or rat liver mitochondria and inhibition against avian myeloblastosis virus reverse transcriptase. The significantly lower cytotoxicity of sakyomicin A as compared with juglone was attributable to its poor membrane transport. The inhibition of reverse transcriptase activity may result from the interaction between a sulfhydryl group in the active center of the enzyme and quinone groups of the naphthoquinones and sakyomicin A.
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PMID:Role of the naphthoquinone moiety in the biological activities of sakyomicin A. 242 91

Thirteen heterocyclic quinones (5 quinoline quinones, 7 isoquinoline quinones, 1 indole quinone) were tested for their effects on avian myeloblastosis virus reverse transcriptase, growth of murine lymphoblastoma L5178Y cells, respiration of rat liver mitochondria and oxidation of NADH by Clostridium kluyveri diaphorase in comparison with those of streptonigrin, in which the quinoline quinone moiety is considered to play a crucial role. Most of the quinoline quinones and isoquinoline quinones inhibited reverse transcriptase to the same extent as streptonigrin with the ID50 values ranging between 1 and 5 micrograms/ml, whereas the ID50 value of the indole quinone derivative, 4,7-dihydro-2,3-dimethylindole-4,7-dione, was 80 micrograms/ml. The cytotoxicities of the quinones were much lower than that of streptonigrin; the ID50 values of the quinones were higher than 0.15 micrograms/ml. In particular, the ID50 value of the ortho-quinoline quinone derivative, 8-methoxy-7-methyl-5,6-dihydroquinoline-5,6-dione, was as high as 16 micrograms/ml, while the 50% inhibition of cell growth was seen in the presence of 0.0025 micrograms/ml streptonigrin. The membrane transport of the quinones was evaluated by comparing the effects on oxygen consumption by mitochondria and oxidation of NADH by bacterial diaphorase, being proven not to be responsible for their lower cytotoxicities.
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PMID:Comparative study on biological activities of heterocyclic quinones and streptonigrin. 244 Aug 40

Inhibition of avian myeloblastosis virus (AMV) reverse transcriptase by natural and synthetic quinones including antibiotics could be accounted for by an oxidation-reduction reaction. The quinones were shown to function as electron acceptors as revealed by the catalytic oxidation of NADH by Clostridium kluyveri diaphorase which was in excellent agreement with enzyme inhibition activity. The kinetics of inhibition of AMV reverse transcriptase by three synthetic quinones with different core structures, i.e., 6-methoxy-5,8-dihydroquinoline-5,8- dione, 5,8-dihydroisoquinoline-5,8-dione and 1,4-naphthoquinone, were studied. These quinones inhibited reverse transcriptase in the same manner as streptonigrin (STN) and were shown to act at a single class of reaction site(s) on the enzyme molecule. In contrast, the quinones with bulky substituents, i.e., 7-(2-nitrophenethylamino)-5,8-dihydroisoquinoline-5,8-dione and 7-methoxy-6-methyl-3-piperidino-5,8-dihydroisoquinoline-5,8-dione, were inactive as inhibitors of reverse transcriptase, whereas they retained competent catalytic activities in the oxidation of NADH by C. kluyveri diaphorase. Based on these observations, the existence of a specific site of interaction on the enzyme molecule, referred to as a quinone pocket, was proposed. The quinone pocket might play a crucial role in the early sequence of events leading to the inhibition of reverse transcriptase by quinones including STN and sakyomicin A (SKM). Access of SKM to a quinone pocket might be restricted due to its bulky structure in the vicinity of the quinone group. This is inferred from unsuccessful inhibition of reverse transcriptase by the quinones with bulky substituents, resulting in much poorer inhibition of reverse transcriptase in spite of more potent electron acceptor activity in the oxidation-reduction system as compared with those of STN.
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PMID:Mechanism of inhibition of reverse transcriptase by quinone antibiotics. II. Dependence on putative quinone pocket on the enzyme molecule. 246 54

Glutathione depletion may play a pivotal role in the pathogenesis of human immunodeficiency virus type-1 (HIV-1) infection. Since certain compounds prevent experimental carcinogenesis by elevating the levels of glutathione and phase II detoxication enzymes, we compared the potencies of several inducers with their ability to inhibit basal levels of HIV-1 replication in H9 cutaneous T-cell lymphoma cells. All monofunctional inducers tested elevated the levels of glutathione and quinone reductase, a marker for phase II enzyme induction. However, only oltipraz [4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione] was effective at inhibiting HIV-1 replication (IC50 = 14.8 +/- 3.1 microM). The antiviral effect of oltipraz was potentiated by 3'-azido-3'-deoxythymidine. Thus, 1,2-dithiole-3-thiones represent a hitherto unrecognized class of anti-HIV-1 agents. Oltipraz behaves kinetically as an irreversible inhibitor of HIV-1 reverse transcriptase in the template-primer binding domain. Oltipraz has been used to treat schistosomiasis in humans and is undergoing clinical evaluation as an anticarcinogen. Thus, oltipraz (and other 1,2-dithiole-3-thiones) may have therapeutic utility in HIV-1-infected individuals, not only because of their antiretroviral activity, but also by preventing the development of HIV-1-associated neoplasms.
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PMID:Oltipraz, an inhibitor of human immunodeficiency virus type 1 replication. 768 14

The aryl hydrocarbon receptor (AHR) is a transcriptional activator of genes encoding a group of drug-metabolizing enzymes, including cytochrome P450 1A1 (CYP1A1), glutathione S-transferase, tumor-associated aldehyde dehydrogenase and quinone reductase. Both the constitutive and inducible expression of these genes in the liver is zonated, i.e., dominant in hepatocytes of the centrilobular region, a poorly understood position-dependent phenomenon. By comparing cell lysates obtained from opposite acinar regions we observed that immunoreactive AHR protein was almost exclusively confined to centrilobular cells. The AHR mRNA, as analyzed from cell lysates by reverse transcriptase polymerase chain reaction, exhibited a similar, although somewhat less pronounced zonation. By contrast, only slight zonation of the AHR nuclear translocator mRNA was observed. Treatment of rats with omeprazole, an atypical nonligand activator of the AHR, caused a zone-specific induction of CYP1A1 in the centrilobular region similar to that seen after pretreatment with the AHR ligand 3-methylcholanthrene. Our results suggest that the zone-restricted expression of AHR protein will allow the constitutive and inducible expression of AHR-regulated genes in the centrilobular region, but will limit their expression in the periportal region.
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PMID:Selective centrilobular expression of the aryl hydrocarbon receptor in rat liver. 899 35

The effect of extracts of scutellariae radix (Scutellaria baicalensis Georgi) and its flavonoids, baicalin, baicalein and wogonin, on induction of quinone reductase (QR) in the Hepa 1c1c7 murine hepatoma cell line was examined. A significant and dose-dependent induction of QR activity was observed in the methanol extract of scutellariae radix and baicalin. HPCL analysis showed that baicalin was contained as a main component in the methanol extract of scutellariae radix, indicating that baicalin may be the major active principle of QR induction mediated by scutellariae radix extract. To elucidate the mechanism of baicalin-mediated induction of QR enzyme activity, the effect on QR mRNA levels in Hepa 1c1c7 cell cultures was investigated. Using reverse transcriptase-polymerase chain reaction techniques, time- and dose-dependent induction of QR mRNA levels by baicalin were demonstrated in Hepa 1c1c7 cells. On the basis of these results, the scutellariae radix extract or baicalin can be regarded as a readily available, promising, novel cancer chemopreventive agent.
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PMID:Induction of quinone reductase by a methanol extract of Scutellaria baicalensis and its flavonoids in murine Hepa 1c1c7 cells. 992 95

Nitric oxide synthase (NOS) containing nerve regeneration can be seen six months after unilateral cavernous nerve neurotomy in rats. However, its molecular mechanism is still unknown. It is believed that growth factors are involved in this phenomenon. In this study we investigated the change of NOS containing nerve fibers and the RNA expression of insulin like growth factor (IGF)-I, nerve growth factor (NGF), transforming growth factor (TGF)-alpha, TGF-beta 1, TGF-beta 2. TGF-beta 3 and NOS on the penis after cavernous nerve neurotomy in rats. Male rats were divided into three groups: (1) sham operation (N = 10); (2) unilateral neurotomy of a 5 mm segment of the cavernous nerve (N = 15); and (3) bilateral neurotomy (n = 15). Electrostimulation of the intact cavernous nerve or pelvic ganglion was performed at one, three and six months. Nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase staining was used to identify NOS in the penile nerve fibers. The gene expression for growth factors and bNOS was investigated in corporal tissue by reverse transcriptase-polymerase chain reaction (RT-PCR) using specific oligonucleotide primers. One month after neurotomy, both unilateral and bilateral neurotomy groups showed a significant decrease in NOS-containing nerve fibers on the dorsal and intracavernosal nerves on the side of neurotomy, and a significantly lower mRNA expression of bNOS, IGF-I and TGF-beta 2. At three months, the number of NOS-containing nerve fibers in the unilateral neurotomy group increased only slightly but at six months those in the intracavernosal nerve increased in a significant amount (P < 0.0001), however mRNA expression of bNOS, IGF-I and TGF-beta 2 showed a significant increase as early as at three months. After bilateral neurotomy, the NOS-positive nerve fibers in the dorsal and intracavernosal nerve were significantly decreased at one month and remained so at six months; no erectile response could be elicited by pelvic ganglion stimulation. In the unilateral neurotomy group at six months, more NOS-positive neurons in the pelvic ganglia were found on the intact side than on the side of the neurotomy (P < 0.003), indicating that the regeneration derives from pelvic ganglion neurons on the intact side. Furthermore, electrostimulation in the unilateral neurotomy group revealed a greater maximal intracavernosal pressure and a shorter latency period at six months than at one month (P < 0.014, P < 0.001, respectively). These data suggest that IGF-I and TGF-beta 2 may play a key role in regeneration of NOS-containing nerve fibers in the dorsal and intracavernosal nerves after unilateral cavernous nerve injury.
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PMID:The role of growth factor on regeneration of nitric oxide synthase (NOS)--containing nerves after cavernous neurotomy in the rats. 1046 23

The molecular mechanism of nitric oxide synthase (NOS)-containing nerve regeneration is still unknown. It is believed that growth factors are involved in this phenomenon. We investigated the change of NOS containing nerve fibers and the mRNA expression of insulin like growth factor (IGF)-I, nerve growth factor (NGF), transforming growth factor (TGF)-alpha, TGF-beta1, TGF-beta2, TGF-beta3, vascular endothelial growth factor (VEGF), endothelial NOS (eNOS) and neuronal NOS (nNOS) on the penis after cavernous nerve neurotomy in rats. Male rats were divided into four groups: (1) sham operation (n = 14); (2) unilateral neurotomy of a 5 mm segment of the cavernous nerve (n = 21); (3) unilateral neurotomy with growth hormone (n = 14); and (4) bilateral neurotomy (n = 21). Electrostimulation of the intact cavernous nerve or pelvic ganglion were performed at one, three and six months. Nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase staining and immunohistochemistry were used to identify NOS in the penis. The gene expression for growth factors, eNOS and nNOS were investigated in corporal tissue by reverse transcriptase-polymerase chain reaction (RT-PCR). One month after neurotomy, both unilateral and bilateral neurotomy groups showed significant decreases in NOS-containing nerve fibers on the dorsal and intracavernosal nerves on the side of neurotomy. Significantly lower mRNA expression of nNOS, IGF-I and TGF-beta2, higher mRNA expression of eNOS and VEGF189 were shown in these groups. At three months, the number of NOS-containing nerve fibers in the unilateral neurotomy group increased only slightly, while the GH-treated group showed a significant increase. At six months, those in the intracavernosal nerve only increased in a significant amount (P < 0.0001), however mRNA expression of nNOS, IGF-I and TGF-beta2 showed a significant increase as early as at three months. After bilateral neurotomy, the NOS-positive nerve fibers in the dorsal and intracavernosal nerve were significantly decreased at one month and remained so at six months; no erectile response could be elicited by pelvic ganglion stimulation. In the unilateral neurotomy group at six months, more NOS-positive neurons in the pelvic ganglia were found on the intact side than on the side of the neurotomy (P < 0.003), indicating that the regeneration derived from pelvic ganglion neurons on the intact side. Furthermore, electrostimulation in the unilateral neurotomy group revealed a greater maximal intracavernosal pressure and a shorter latency period at six months than at one month (P < 0.014, P < 0.001, respectively). These data suggest that IGF-I and TGF-beta2 may play a key role in the regeneration of nNOS-containing nerve fibers in the dorsal and intracavernosal nerves, and eNOS increases temporarily in the intracavernous involving VEGF189 after unilateral cavernous nerve injury.
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PMID:IGF-I and TGF-beta2 have a key role on regeneration of nitric oxide synthase (NOS)-containing nerves after cavernous neurotomy in rats. 1055 3

NAD(P)H:quinone oxidoreductase (NQO1) and dihydronicotinamide riboside:quinone oxidoreductases (NQO2) are cytosolic flavoproteins that catalyze the two-electron reduction of quinones and quinoid compounds to hydroquinones, thereby promoting detoxification and preventing the formation of highly reactive oxygen species, which lead to DNA and cell damage. Two NQO isoforms, designated NQO1 and NQO2, have been cloned and sequenced. To elucidate their role in carcinogenesis, the gene expression of human NQO1 and NQO2 in paired normal and tumor tissue samples was examined. Quantitative triplex reverse transcriptase polymerase chain reaction was employed to analyze NQO1 and NQO2 mRNA expression in normal hepatic and biliary tissue as well as in cholangiocellular carcinomas (CCC), hepatocellular carcinomas (HCC), and focal nodular hyperplasias (FNH). Coexpression of beta-actin RNA was used as an internal reference standard and linear ranges of transcript amplification were established for each sample. In normal hepatocellular tissue, the two NQO isoforms were differentially regulated, with a higher expression of NQO2 than NQO1. Malignant hepatocellular tissue (HCC), however, displayed up-regulation of NQO1 and down-regulation of NQO2. Regulation of either transcript was not seen in benign hepatocellular tumor tissue (FNH), which indicates a reciprocal control of NQO genes in hepatocarcinogenesis. Normal biliary tissue expressed a significantly higher level of NQO1 transcripts compared with normal liver, whereas biliary NQO2 levels were significantly lower than in hepatocellular tissue. Comparing the levels of expression in normal and malignant biliary tissue (CCC), no significant differences were noted between the expression levels of either transcript. Thus, this study provides evidence for differential hepatic and biliary regulation of both NQO1 and NQO2.
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PMID:Differential gene expression of NAD(P)H:quinone oxidoreductase and NRH:quinone oxidoreductase in human hepatocellular and biliary tissue. 1180 56

The cytotoxicity and apoptosis-inducing activity of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and 2-tert-butyl-4-methylphenol (BMP) and the mixture of BHA and BHT (BHA/BHT) (1:1, molar ratio) were investigated, using human promeylocytic leukemia cell lines (HL-60) and human squamous cell carcinoma cell lines (HSC-2). The 50% cytotoxic concentration (CC50) declined in the order of BHA, BHT (0.2-0.3 mM) > BHA/BHT (0.04-0.07 mM) > BMP (0.02-0.05 mM). The addition of antioxidants (N-acetyl-Lcysteine, sodium ascorbate, catalase) reduced the cytotoxicity of BHA/BHT or BMP against HSC-2 cells, but not that of BHA or BHT, whereas the addition of NADH, a quinone reductase to BMP, enhanced the cytotoxicity. These findings suggested that the cytotoxicity of BHA/BHT and BMP might be caused by reactive intermediates. BHA-induced cytotoxicity was enhanced by horseradish peroxidases, suggesting that BHA was oxidizable and produced cytotoxic BHA radicals. Internucleosomal DNA fragmentation of HL-60 cells was preferably induced by BHA/BHT and BMP, followed by BHA. The MnSOD mRNA expression in HL-60 cells assayed by reverse transcriptase-polymerase chain reaction was highly inhibited by BHA/BHT or BMP, accompanied by the change in the electrophoretic mobility of MnSOD on polyacryamide gel. These compounds activated caspase-3, 8 and 9 in HL-60 cells. Activations of caspases, particularly caspase-3, declined in the order of BHA/BHT > BHA > BMP > BHT. The most cytotoxic BMP activated caspase-3 activity to the least extent, possibly in part due to the occurrence of necrosis. The great cytotoxicity and apoptosis induction by BHA/BHT may be due to reactive intermediates derived from the interaction between BHA phenoxyl radical and BHT or BHT phenoxyl radical.
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PMID:Cytotoxicity and apoptosis induction by butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT). 1498 15


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