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 effect of long-term GSH administration on aflatoxin B1 (AFB1)-induced carcinogenesis in the livers of male Wistar II rats was evaluated. No significant effect of an 11 months period of reduced glutathione (GSH) administration was observed concerning both the survival curve and the incidence of liver tumors. Liver tissues of all animals were bearing tumors or nodular lesions 24 months after AFB1 treatment, regardless of GSH treatment. The capacity of the GSH conjugation system was elevated in the liver tissue of AFB1-treated animals both by an increase of GSH content and an increase of the specific activities of several GSH S-transferase isoenzymes. Likewise the specific activities of GSH related enzymes as GSSG reductase and gamma-glutamyltransferase (gamma-GT) and the activity of the GSH independent detoxication system NAD(P)H:quinone oxidoreductase were increased in the AFB1-treated livers, there was no significant effect of GSH treatment. These results demonstrate that long-term GSH treatment has no effect on the survival of AFB1-pretreated male rats on the incidence of liver tumors and on the activities of drug metabolizing systems. The hepatic detoxication capacity 24 months after AFB1 treatment is elevated.
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PMID:Lack of effect of long-term glutathione administration on aflatoxin B1-induced hepatoma in male rats. 392 36

The cytotoxicity of menadione (2-methyl-1,4-naphthoquinone) and benzo(a)pyrene-3,6-quinone (BP-3,6-Q) was tested in cultures of adult rat hepatocytes and human fibroblasts. Menadione induced DNA strand breaks, cell membrane damage and depletion of reduced glutathione (GSH) in both hepatocytes and fibroblasts. In fibroblasts, effects on both DNA and membrane integrity were potentiated by the presence of dicoumarol, a specific inhibitor of the 2-electron reduction of quinones by DT-diaphorase, whereas in hepatocytes only the cell membrane damage was sensitive to dicoumarol. Results indicate that menadione toxicity is mediated via 1-electron reduction, although in hepatocytes different reactive species may be responsible for damage to DNA and to the membrane. BP-3,6-Q induced DNA strand breaks in fibroblasts at concentrations as low as 1 microM. The extent of DNA damage was insensitive to dicoumarol. Even after GSH depletion and inhibition of glucuronidation and sulphate conjugation, BP-3,6-Q caused no DNA damage in hepatocytes. In contrast to menadione, BP-3,6-Q did not induce cell membrane leakage or decrease in GSH levels in either hepatocytes or fibroblasts. These studies show the complexity of the metabolic pathways involved, in terms of activation and detoxification processes, in the toxicity of quinones.
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PMID:Induction of cell damage by menadione and benzo(a)pyrene-3,6-quinone in cultures of adult rat hepatocytes and human fibroblasts. 406 Jan 94

1. Starvation for 3 days produces a decrease in methaemoglobin-reductase and glutathione-reductase activities, but it does not alter the glucose 6-phosphate-dehydrogenase activity of the rat erythrocyte. 2. The feeding of a protein-free diet for 11 days causes greater changes in the first two enzymes and also a diminution of the third. Under this experimental condition slight decreases in protein and haemoglobin contents were noted. 3. The experimental animals did not show methaemoglobinaemia, probably because the activity of methaemoglobin diaphorase is preserved. 4. The GSH content was not affected but the stability of the tripeptide in the presence of an oxidizing agent was diminished.
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PMID:Studies on the oxidation-reduction systems of the erythrocyte. 437 99

Formation of excited species such as singlet molecular oxygen during redox cycling (one-electron reduction-oxidation) was detected by low-level chemiluminescence emitted from perfused rat liver and isolated hepatocytes supplemented with the quinone, menadione (vitamin K3). Chemiluminescence was augmented when the two-electron reduction of the quinone catalyzed by NAD(P)H:quinone reductase was inhibited by dicoumarol, thus underlining the protective function of this enzyme also known as DT-diaphorase. Interference with NADPH supply by inhibition of energy-linked transhydrogenase by rhein or of mitochondrial electron transfer by antimycin A led to a depression in the level of photoemission. Unexpectedly, glutathione depletion of the liver led to a lowering of chemiluminescence elicited by menadione, whereas conversely the depletion of glutathione led to increased chemiluminescence levels when a hydroperoxide was added instead of the quinone. As the GSH conjugate of menadione, 2-methyl-3-glutathionyl-1,4-naphthoquinone, studied with microsomes, was shown also to be capable of redox cycling, we conclude that menadione-induced chemiluminescence of the perfused rat liver does not only arise from menadione itself but from the menadione-GSH conjugate as well. Therefore, the conjugation of the quinone with glutathione is not in itself of protective nature and does not abolish semiquinone formation. A biologically useful aspect of conjugate formation resides in the facilitation of biliary elimination from the liver. Nonenzymatic formation of the conjugate from menadione and GSH in vitro was found to be accompanied by the formation of aggressive oxygen species.
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PMID:Hepatic low-level chemiluminescence during redox cycling of menadione and the menadione-glutathione conjugate: relation to glutathione and NAD(P)H:quinone reductase (DT-diaphorase) activity. 619 66

The mechanism(s) of toxicity of 1-naphthol and two of its possible metabolites, 1,2- and 1,4-naphthoquinone, to freshly isolated rat hepatocytes has been studied. 1-Naphthol and both naphthoquinones exhibited a dose-dependent toxicity to hepatocytes. [1-14C]-1-Naphthol was metabolised by hepatocytes predominantly to its glucuronic acid and sulphate ester conjugates, but small amounts of covalently bound products were also formed. Blebbing on the surface of the hepatocytes was observed following exposure to 1-naphthol and the naphthoquinones, together with a dose-dependent decrease in intracellular glutathione (GSH), which preceded the onset of cytotoxicity. The toxicity of 1-naphthol and the naphthoquinones was potentiated by dicoumarol, an inhibitor of DT-diaphorase (NAD(P)H:quinone oxidoreductase). This enhanced toxicity was accompanied by a greater amount of surface blebbing, an increased depletion of intracellular GSH, particularly in the case of 1-naphthol and 1,4-naphthoquinone, and a decreased metabolism of 1-naphthol to its conjugates with variable effects on the amount of covalently bound products formed. These results support the suggestion that the toxicity of 1-naphthol may be mediated by the formation of 1,2-naphthoquinone and/or 1,4-naphthoquinone, which may then be metabolised by one electron reduction to naphthosemiquinone radicals. These, in turn, may covalently bind to important cellular macromolecules or enter a redox cycle with molecular oxygen thereby generating active oxygen species. Both of these processes appear to play a role in producing the cytotoxic effects of 1-naphthol.
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PMID:Mechanisms of toxic injury to isolated hepatocytes by 1-naphthol. 620 Jan 19

The role of various enzymes and biological molecules on the activation and deactivation of the metabolites of phenol was investigated in vitro. Phenol, the major metabolite of benzene, is metabolized to hydroquinone and catechol. Activation of these metabolites and deactivation of their oxidized forms was assessed by the amount of covalent binding to microsomal protein. [14C]Phenol and NADPH were incubated with hepatic microsomes isolated from phenobarbital-pretreated guinea pigs, and 2.33 nmoles of hydroquinone and 0.12 nmole of catechol were formed per minute per milligram of microsomal protein. Covalent binding of the metabolites to microsomal protein incubated with microsomes isolated from guinea pigs pretreated with phenobarbital was 252 pmoles bound/min/mg; with microsomes from untreated guinea pigs, covalent binding was 146 pmoles bound/min/mg. Covalent binding was inhibited greater than 90% with the addition of N-octylamine, ascorbate, or GSH. The addition of superoxide dismutase inhibited covalent binding with microsomes isolated from phenobarbital-pretreated guinea pigs 35% but did not inhibit it with microsomes isolated from untreated animals. Partially purified guinea pig hepatic DT-diaphorase [NAD(P)H (quinone acceptor) oxidoreductase, EC 1.6.99.2] inhibited covalent binding 70%. This effect was reversed in the presence of dicumarol, a specific inhibitor of DT-diaphorase. DT-diaphorase present in the 10(5) X g supernatant fraction was also active in inhibiting covalent binding but only after the removal of endogenous reduced glutathione. This effect could also be reversed by dicumarol. The addition of diaphorase (NADH:lipoamide oxidoreductase, EC 1.6.4.3) partially purified from Clostridium kluyveri inhibited covalent binding 86%. The addition of hydrogen peroxide and horseradish peroxidase (peroxidase, EC 1.11.17) or myeloperoxidase(s) increased covalent binding 30-fold and 6-fold, respectively. Ascorbate decreased this binding greater than 95%. These results indicate that hydroquinone, catechol, and phenol as well as their oxidized forms can be activated or deactivated by several of the above model systems. These systems may play a role in the myelotoxicity of benzene by modulating covalent binding.
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PMID:DT-diaphorase and peroxidase influence the covalent binding of the metabolites of phenol, the major metabolite of benzene. 674 27

The diurnal rhythms of the microsomal flavoprotein NADPH-cytochrome c reductase activity, of diaphorase and of succinic dehydrogenase are presented. Minimum levels are ascertained at 09(00), maximum levels at 21(00). The concentration of mitochondrial radicals as a function of the time of day is also demonstrated. Here too the minimum is at 09(00) and the maximum between 15(00) and 21(00). On the other hand, GSH levels are found to be high between 09(00) and 12(00) and low in the evening. Thus a causative relationship between the concentration of cellular radicals, which originate in flavin enzymes, and the concentration of the tripeptide glutathione is assumed.
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PMID:Flavin enzymes, mitochondrial radicals and reduced glutathione in daily rhythmic dependency. 677 1

We have previously shown that oleanolic acid (OA) protects mice against the hepatotoxicity of carbon tetrachloride, acetaminophen, bromobenzene, thioacetamide, furosemide, phalloidin, colchicine, cadmium, D-galactosamine and endotoxin. This study was designed to examine whether OA modulates hepatic toxicant-activating and detoxifying systems as a means of protection. Mice were treated with OA (100 and 200 mumol/kg s.c.) for 3 days, and liver microsomes and cytosols were prepared 24 hr after the last dose. OA produced a dose-dependent reduction in liver microsomal cytochrome P450 (P450) levels (25-37%) and cytochrome b5 (15-21%) content, but had no effect on NADPH-cytochrome c reductase activity. OA treatment also decreased several P450 enzyme activities, such as coumarin 7-hydroxylation (45%), 7-pentoxyresorufin O-dealkylation (35%), 7-ethoxyresorufin O-dealkylation (25%) and chlorzoxazone 6-hydroxylation (20%). Treatment of mice with OA decreased caffeine N3-demethylation (40%), but had no effect on caffeine 8-hydroxylation. OA treatment decreased testosterone 6 alpha- and 15 alpha-hydroxylation (40-50%) and androstenedione formation (35%), but slightly increased testosterone 1 alpha/beta-, 2 beta- and 6 beta-hydroxylation. Consistent with enzyme activities, OA decreased the amounts of mouse liver CYP1A and CYP2A enzymes, but had no appreciable effect on CYP3A enzymes, as determined by immunoblotting with antibodies against rat P450 enzymes. OA treatment slightly increased liver glutathione (GSH) content and the activity of GSH S-transferases toward 1-chloro-2,4-dinitrobenzene, but had no effect on GSH peroxidase and GSH reductase. The activities of superoxide dismutase and DT-diaphorase were unaffected by OA treatment. At the high dose of OA, catalase activity was decreased by 20%.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of oleanolic acid on hepatic toxicant-activating and detoxifying systems in mice. 747 65

In this study, we have characterized quinone reductase (QR), glutathione (GSH), glutathione S-transferase (GST) and their induction by a chemoprotector, 1,2-dithiole-3-thione (D3T), in the human myeloid cell lines ML-1 and HL-60. In addition, we also examined the toxicity of hydroquinone (HQ), a benzene metabolite, to these two cell lines. Both of the cell lines contain a basal level of cellular GSH, which is similar in the two cell lines. Although ML-1 cells contain much higher QR specific activity than HL-60 cells, which are relatively QR deficient, the GST specific activity of ML-1 cells is 1.8 times less than that of HL-60 cells. Immunoblot experiments showed that the GST in these two cell lines is GST pi. In addition, HL-60 cells exhibit 4.5 times more myeloperoxidase specific activity than ML-1 cells. Inclusion of D3T in the cultures could induce significant increases in cellular GSH content and QR activity, but not GST activity in either cell line. Treatment with HQ caused both inhibition of cell proliferation and loss of cell viability in these two myeloid cell lines. HQ treatment also resulted in a significant depletion of cellular GSH, which preceded the loss of cell viability. Pretreatment of both cell lines with buthionine sulfoximine, an inhibitor of GSH biosynthesis, markedly increased HQ-induced toxicity. In contrast, the presence of dicumarol, a QR inhibitor, failed to potentiate HQ-induced toxicity in ML-1 cells. On the other hand, pretreatment of these two myeloid cell lines with D3T significantly protected against HQ-induced inhibition of cell proliferation and cell death. Therefore, the above results suggest that GSH but not QR is an important factor involved in the toxicodynamics of HQ in these myeloid cells.
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PMID:Characterization of quinone reductase, glutathione and glutathione S-transferase in human myeloid cell lines: induction by 1,2-dithiole-3-thione and effects on hydroquinone-induced cytotoxicity. 751 Dec

Oral exposure of DBA/2 mice to benzo[a]pyrene (BP) has been shown to result in hematotoxicity which is manifested as aplastic anemia and leukemia. Since normal hematopoiesis is regulated by bone marrow stromal cells, in this study we have characterized the bone marrow stromal toxicity induced by BP and BP-derived metabolites, particularly quinones. Incubation of stromal cells with various concentrations of BP-1,6-, 3,6-, 6,12-, or 7,8-quinone for 24 hr resulted in a significant decrease of cell survival in a concentration-dependent manner, while cells treated with BP or BP-7,8-dihydrodiol did not exhibit any significant loss of cell survival. Among the BP quinones examined, BP-1,6-quinone was the most cytotoxic to stromal cells. The cytotoxicity induced by BP-1,6-quinone also exhibited a time-dependent relationship. Pretreatment of stromal cells with 1,2-dithiole-3-thione (D3T) resulted in a significant induction of both cellular reduced glutathione (GSH) content and quinone reductase (QR) activity in a concentration-dependent manner. However, D3T pretreatment did not offer any protection against BP-1,6-quinone-induced toxicity. Furthermore, dicumarol, a potent inhibitor of QR, or buthionine sulfoximine, a specific inhibitor of GSH biosynthesis, did not potentiate BP-1,6-quinone-induced cytotoxicity was not altered. However, incubation of stromal cells with BP-1,6-quinone resulted in a significant depletion of cellular ATP content and mitochondrial morphological changes, which preceded the loss of cell survival. In addition to BP-1,6-quinone, other cytotoxic BP quinones also exhibited a capacity to deplete cellular ATP level in stromal cells, while BP, which was not cytotoxic to stromal cells, did not elicit any significant decrease in cellular ATP level. These observations suggest that mitochondria may be a potential target of BP quinones. Overall, the above results indicate that neither cellular GSH and QR nor reactive oxygen species appear to be involved in BP quinone-induced stromal cell injury and that BP quinones may elicit cytotoxicity to stromal cells through directly disrupting mitochondrial energy metabolism.
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PMID:Characterization of benzo[a]pyrene quinone-induced toxicity to primary cultured bone marrow stromal cells from DBA/2 mice: potential role of mitochondrial dysfunction. 753 Aug 64


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