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

Wefers, Heribert; Sies, Helmut

doi:10.1016/0003-9861(83)90244-8

Cited by 173 publications

(51 citation statements)

References 14 publications

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“…by NADPH oxidase. To check whether this mechanism was operating in N11 cells, we measured the PPP activity in cells stimulated with menadione (which exerts an oxidative stress by generating ROS through its redox cycling and by forming a conjugate with glutathione) (34) or with H 2 O 2 ; in both conditions, the ROS synthesis was independent of NADPH oxidase activity. The coincubation with DPI significantly inhibited both basal and oxidative stressstimulated PPP, ruling out that DPI inhibits the PPP activity by blocking NADPH oxidase and suggesting that such inhibition is exerted at a different level, more likely at the G6PD step.…”

Section: Resultsmentioning

confidence: 99%

Diphenyleneiodonium Inhibits the Cell Redox Metabolism and Induces Oxidative Stress

Riganti

Gazzano

Polimeni

et al. 2004

Journal of Biological Chemistry

178

133

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Diphenyleneiodonium (DPI) and the structurally related compound diphenyliodonium (DIP) are widely used as inhibitors of flavoenzymes, particularly NADPH oxidase. Here we report further evidence that DPI and DIP are not specific flavin binders. A 3-h incubation of N11 glial cells with DPI significantly inhibited in a dosedependent way both the pentose phosphate pathway and the tricarboxylic acid cycle. In parallel, we observed a dose-dependent increase of reactive oxygen species generation and lipoperoxidation and increased leakage of lactate dehydrogenase activity in the extracellular medium. The glutathione/glutathione disulfide ratio decreased, whereas the efflux of glutathione out of the cells increased. This suggests that DPI causes an augmented oxidative stress and exerts a cytotoxic effect in N11 cells. Indeed, the cells were protected from these events when loaded with glutathione. Similar results were observed using DIP instead of DPI and also in other cell types. We suggest that the DPI-elicited inhibition of the pentose phosphate pathway and tricarboxylic acid cycle may be mediated by the blockade of several NAD(P)-dependent enzymes, such as glucose 6-phosphate dehydrogenase, glyceraldehyde 3-phosphate dehydrogenase, and lactate dehydrogenase. In light of these results, we think that some effects of DPI or DIP in in vitro and in vivo experimental models should be interpreted with caution. Diphenyleneiodonium (DPI) 1 and the structurally related compound diphenyliodonium (DIP) are widely used as uncompetitive inhibitors of flavoenzymes. Firstly identified as a hypoglycemic agent able to block gluconeogenesis and respiration in rat liver (1), DPI has been subsequently shown to inhibit the activity of NADH:ubiquinone oxidoreductase (2, 3), NADPH oxidase (4 -6), nitric-oxide synthase (7), xanthine oxidase (6), and NADPH cytochrome P450 oxidoreductase (8). DPI and other iodonium derivatives have been shown to react via a radical mechanism, whereby an electron is abstracted from FAD or FMN to form a radical, which then adds back to the flavin to form covalent, phenylated adducts (9). Also, heme groups, such as the heme b of NADPH oxidase, have been found to react with DPI and DIP (10).In most experimental works of the last years, DPI or DIP have been used as inhibitors of NADPH oxidase. NADPH oxidases are a group of plasma membrane-associated enzymes found in a variety of cells of mesodermal origin. The most thoroughly studied is the leukocyte isoform, which catalyzes the production of superoxide (O 2 . ) by the one-electron reduction of oxygen, using NADPH as the reducing agent (11). The O 2 .generated by NADPH oxidase serves as the starting material for the production of a vast assortment of reactive oxidants used by phagocytes to kill invading microorganisms or tumor cells (11). A low activity NADPH oxidase is present in a variety of nonphagocytic cells, wherein this enzyme is a source of second messengers. It has been postulated, for instance, that the O 2 . generated by the aorta functions as a blood ...

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Section: Resultsmentioning

confidence: 99%

Diphenyleneiodonium Inhibits the Cell Redox Metabolism and Induces Oxidative Stress

Riganti

Gazzano

Polimeni

et al. 2004

Journal of Biological Chemistry

178

133

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“…Previous studies have demonstrated that enhancement of menadione-mediated proteolysis by dicumarol suggests that the hydroquinone form of menadione is a nontoxic species or is rapidly conjugated and excreted from the cell and does not activate a cell death pathway (45). In nude mouse models of pancreatic cancer, antitumor quinones, including mitomycin C and doxorubicin analogues, have demonstrated inhibition of growth (46,47).…”

Section: Discussionmentioning

confidence: 99%

Treatment of Pancreatic Cancer Cells with Dicumarol Induces Cytotoxicity and Oxidative Stress

Lewis

Ough

et al. 2004

Clinical Cancer Research

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“…Although conjugation of electrophiles with GSH usually results in detoxication and their subsequent elimination as mercapturic acids, several examples exist where conjugation of GSH with electrophiles results in preservation or enhancement of biological (re)activity (Monks and Lau, 1998). For example, quinone-thioethers retain the ability to redox cycle and produce reactive oxygen species and to arylate tissue macromolecules (Wefers and Sies, 1983;Kleiner et al, 1998a,b). Quinone-thioethers also inhibit enzymes that utilize GSH as a cosubstrate and, in particular, the 5-S-glutathionyl conjugates of dopamine and ␣-methyldopa inhibit human GSH S-transferases (Ploemen et al, 1994).…”

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confidence: 99%

Accumulation of Neurotoxic Thioether Metabolites of 3,4-(±)-Methylenedioxymethamphetamine in Rat Brain

Erives¹,

Lau²,

Monks³

2007

J Pharmacol Exp Ther

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The serotonergic neurotoxicity of 3,4-(Ϯ)-methylenedioxymethamphetamine (MDMA) appears dependent upon systemic metabolism because direct injection of MDMA into the brain fails to reproduce the neurotoxicity. MDMA is demethylenated to the catechol metabolite N-methyl-␣-methyldopamine (N-Me-␣-MeDA). Thioether (glutathione and N-acetylcysteine) metabolites of N-Me-␣-MeDA are neurotoxic and are present in rat brain following s.c. injection of MDMA. Because multidose administration of MDMA is typical of drug intake during rave parties, the present study was designed to determine the effects of multiple doses of MDMA on the concentration of neurotoxic thioether metabolites in rat brain. The serotonergic neurotoxicity 3,4-(Ϯ)-methylenedioxymethamphetamine (MDMA, Ecstasy) and 3,4-(Ϯ)-methylenedioxyamphetamine (MDA) is dependent on the route of administration (O'Shea et al., 1998). Direct injection of MDMA and MDA into the brain fails to reproduce the acute or long-term neurotoxic effects evident following peripheral administration of these drugs (Schmidt et al., 1987;Paris and Cunningham, 1992), suggesting that systemic (liver) metabolism contributes to the neurotoxicity of MDMA and MDA. Indeed, although MDMA targets the serotonergic system in humans, nonhuman primates, and rats, the finding that MDMA does not affect the serotonergic system in mice but rather targets the dopaminergic system has been attributed to metabolic differences between species (Logan et al., 1988;Escobedo et al., 2005). Perhaps the most convincing evidence that peripheral metabolism of MDMA is required for neurotoxicity was provided by the work of Esteban et al. (2001). In this study, MDMA was perfused into the hippocampus in amounts sufficient to give rise to the range of concentrations observed following peripheral administration of neurotoxic doses of MDMA. After perfusion, acute monoamine release was observed in the absence of long term depletions in 5-HT levels. These data are consistent with the hypothesis that peripheral generation of neurotoxic metabolites contributes to MDMA-induced serotonergic neurotoxicity.MDMA is N-demethylated to MDA and O-demethylenated to N-methyl-␣-methyldopamine (N-Me-␣-MeDA) (Fig. 1) (Lin et al., 1992). N-Demethylation in humans is a minor metabolic pathway (ϳ10%), but ␣-MeDA is a metabolite of both MDMA and MDA. Isoenzymes belonging to the CYP2D subfamily, and the CYP2B or CYP3A1 isoforms, catalyze the low-and high-K m O-demethylenation reactions, respectively (de la Torre et al., 2004). The catecholamine metabolites are very unstable and are either conjugated with sulfate/glucArticle, publication date, and citation information can be found at

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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

Cited by 173 publications

References 14 publications

Diphenyleneiodonium Inhibits the Cell Redox Metabolism and Induces Oxidative Stress

Diphenyleneiodonium Inhibits the Cell Redox Metabolism and Induces Oxidative Stress

Treatment of Pancreatic Cancer Cells with Dicumarol Induces Cytotoxicity and Oxidative Stress

Accumulation of Neurotoxic Thioether Metabolites of 3,4-(±)-Methylenedioxymethamphetamine in Rat Brain

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