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PubMed1986

Dose-dependent study of the effects of acute lindane administration on rat liver superoxide anion production, antioxidant enzyme activities and lipid peroxidation.

The administration of single i.p. doses of lindane (20, 40, 60 and 80 mg/kg) to rats produced a progressive increase in the liver microsomal content of cytochrome P-450 and in the rate of superoxide anion generation, as measured by adrenochrome formation. A dose-dependent increase in lipid peroxidation of liver homogenates, assessed by measuring thiobarbituric acid reactants, was also found. Lindane treatment did not alter the activity of liver glucose-6-phosphate dehydrogenase, glutathione reductase or glutathione peroxidase, while that of superoxide dismutase and catalase was significantly reduced. These changes were accompanied by a progressive liver steatosis. The collected metabolic data were interpreted in terms of a causal relationship between an increase in superoxide radical generation, secondary to cytochrome P-450 induction and a resulting increase in lipid peroxidation. The decrease in superoxide dismutase and catalase activities is likely to contribute to the increased levels of lipid peroxidation in view of their antioxidant properties.

Animals↗

PubMed1995

Scavenging of neutrophil-derived superoxide anion by 1-hydroxyphenazine, a phenazine derivative associated with chronic Pseudomonas aeruginosa infection: relevance to cystic fibrosis.

The airways of cystic fibrosis patients colonised by Pseudomonas aeruginosa contain the redox active phenazine derivative, 1-hydroxyphenazine (OHP). As the presence of reactive oxygen species is of importance to tissue damage in cystic fibrosis, OHP was investigated for its ability to reduce molecular oxygen to superoxide. In the presence of NADPH, OHP reduced cytochrome c in a dose-dependent manner. This effect was not inhibited by superoxide dismutase and demonstrates an electron transport role for OHP. The OHP/NADPH system was unable to reduce molecular oxygen to superoxide as judged by an inability to oxidase epinephrine to adrenochrome. However, using lucigenin-enhanced chemiluminescence to detect superoxide, it was found that pathophysiologically relevant concentrations of OHP (5-25 microM) effectively scavenged superoxide from a xanthine/xanthine oxidase system. Similarly, in the presence of OHP, superoxide availability from contact-activated neutrophils was substantially reduced. It is concluded that OHP is an efficient scavenger of superoxide and that electron transfer from superoxide to OHP represents a major mechanism for reduction of OHP in vivo. Reduced OHP has the potential to alter cellular function by participating in the reduction of iron-containing proteins and in this manner contribute to the pathogenesis of P. aeruginosa infection in cystic fibrosis.

Acridines↗

PubMed2005

Carbon monoxide inhibits superoxide dismutase and stimulates reactive oxygen species production by Desulfovibrio desulfuricans 1388.

The hypothesis that oxidative stress characterized by enhanced superoxide generation underlies the toxicity of some factors to living organisms has been investigated. It is shown that CO (5-6% in gas phase) changed some growth parameters (mu, t(d)) of the sulfate-reducing bacterium Desulfovibrio desulfuricans 1388. Enhanced O(2)(-) generation registered by EPR spectroscopy and adrenochrome method was observed when cells were incubated under CO. The SOD activity in cells from the exponential growth phase growing under CO was decreased 1.5-fold compared with the control cells growing under Ar. SOD activities in cells from the stationary growth phase growing with or without CO were comparable. The results support the concept that CO toxicity for sulfate-reducing bacteria is an oxidative stress that arises in cells oxidizing CO to CO(2).

Journal Article↗

PubMed2004

Protective effect of taurine against free radicals damage in the rat myocardium.

Free radicals are highly cytotoxic to the heart and are involved in ischemia/reperfusion injury. In this study, we tested the ability of taurine to neutralize the deleterious effects of free radicals generated ex vivo and in vitro. Taurine was added at a concentration of 0.1 mM to the drinking water of experimental rats during 6 months. The animal hearts were then isolated and submitted to regional ischemia and reperfusion; ventricular fibrillation was significantly reduced as compared to a control group of non-treated animals. Moreover, at a concentration of 1 mM, taurine provided significant cardio-protection against the deleterious effect of free radicals generated by the electrolysis of Krebs-Henseleit buffer. When isolated hearts were perfused with electrolysed buffer, extensive fiber necrosis occurred, as observed by staining with nitro blue tertrazolium, a soluble dye which yields a dark blue formazan stain in the presence of reducing agents This stain was barely detectable when taurine was added to the perfusing electrolysed buffer. To further understand the protecting mechanism of taurine, we used xanthine-xanthine-oxidase as a superoxide (O2-) generating system and monitored the O2- through yield O2--dependent cytochrome c reduction. We demonstrated that taurine did not affect this system, which indicated that it did not scavenge O2- directly. On the other hand, taurine inhibited the auto-oxidation of adrenaline to adrenochrome at pH 7.8 where this auto-oxidation is O2--independent and superoxide dismutase insensitive. We thus conclude that taurine acts as a potent, but non-specific, scavenger of free radicals that cause heart damage and protects against reperfusion-induced ventricular

Administration, Oral↗

PubMed2006

Evaluation of Pluchea carolinensis extracts as antioxidants by the epinephrine oxidation method.

Many methods have been used to evaluate synthetic and natural products as hydroxyl radical scavengers. In this study a spectrophotometric method to evaluate the scavenger activity of the hydroxyl radical produced in Fenton reaction is proposed. The oxidation of l-epinephrine to adrenochrome permitted the detection of the hydroxyl radical by spectrophotometry and its possible scavenging by hydroquinone, a well known antioxidant. The method was used to evaluate the antioxidant activity of Pluchea carolinensis leaves.

Antioxidants↗

PubMed2004

Factors affecting determination of superoxide anion generated by mitochondria from barley roots after anaerobiosis.

During the post-hypoxic period, symptoms of oxidative stress and activation of enzymatic and non-enzymatic antioxidant systems were observed in several plant tissues. In the roots, mitochondrial respiratory chain is the main source of ROS. Superoxide anion radical is formed in the mitochondrial electron-transport chain at the level of Complexes I and III. The purpose of this work was to estimate superoxide anion production by the mitochondria isolated after a period of hypoxic treatment. Seedlings of barley (Hordeum vulgare L.) were grown on a nutrient medium flushed for 5d with air (control) or nitrogen (hypoxia) and then transferred for 24h to aerated medium (post-hypoxia). Production of superoxide anion by the mitochondria was measured by SOD-inhibitable oxidation of adrenaline to adrenochrome with NADH as a respiratory substrate. Hypoxic treatment increased mitochondrial activity but decreased mitochondrial superoxide anion appearance outside the mitochondrial membrane as compared to the mitochondria isolated from the roots continuously grown on aerated medium. The result of lower superoxide anion determination is attributed to increased antioxidants concentration during hypoxia. This was confirmed by inhibition of O2- production by exogenous GSH and stimulation by addition of 1-chloro-2,4-dinitrobenzene (CDNB), which depleted endogenous mitochondrial GSH.

Anaerobiosis↗

PubMed2004

Oxidative stress markers in aqueous humor of glaucoma patients.

PURPOSE: Oxidative stress and antioxidant status in eye tissues may be associated with glaucomatous damage. The aim of this study was to establish the antioxidant status of aqueous humor of patients with primary open-angle glaucoma. For this purpose the authors measured the total reactive antioxidant potential (TRAP) and the activities of the antioxidant enzymes superoxide dismutase (SOD), catalase, and glutathione peroxidase. DESIGN: Case control study. METHODS: Aqueous humor was obtained at the time of surgery from 24 patients with glaucoma and 24 cataract patients; TRAP was measured by chemiluminescence. Activities of the antioxidant enzymes were measured spectrophotometrically. Superoxide dismutase activity was determined by inhibition of the rate of adrenochrome formation at 480 nm. Catalase activity was evaluated by decrease of H(2)O(2) absorbance at 240 nm. Glutathione peroxidase (GPx) activity was determined following nicotinamide adenine dinucleotide phosphate oxidation at 340 nm. RESULTS: Total reactive antioxidant potential value of the cataract group was 124 +/- 5 micromol/l Trolox. This value was significantly decreased, by 64%, in glaucoma patients. An increase of 57% in SOD activity was observed in glaucoma patients when compared with cataract patients (41.7 +/- 2.7 U SOD/ml). Glutathione activity was threefold higher in glaucoma patients than in the cataract group (6.1 +/- 0.6 U/ml). No significant changes were found in catalase levels. CONCLUSIONS: Oxidative stress may lead to an induction of antioxidant enzymes and contribute to TRAP decrease. Superoxide dismutase, GPx activities, and TRAP may be useful oxidative stress markers in aqueous humor of glaucoma patients.

Adult↗

PubMed1975

Metabolic arrest of the ischemic heart.

Procaine, hypocalcemia, magnesium, fluoride, adrenochrome, and tetrodotoxin have been used to induce metabolic arrest of the heart and increase its tolerance to ischemia. Prolonged periods of ischemic cardiac arrest without measurable deterioration of cardiac function are possible. The application of these techniques in the repair of intracardiac lesions deserves further study.

Adenosine Triphosphate↗

PubMed1998

Ubiquinone-0 (2,3-dimethoxy-5-methyl-1,4-benzoquinone) as effective catalyzer of ascorbate and epinephrine oxidation and damager of neuroblastoma cells.

The kinetics of ascorbate (AscH ) and epinephrine (EP) oxidation in the presence of 2,3-dimethoxy-5-methyl-1,4-benzoquinone (UQ) were studied in 0.05 M phosphate buffer, pH 7.4, at 37 degrees C by using a Clark electrode and ESR techniques. UQ at nanomolar concentrations displayed a pronounced catalytic effect on AscH oxidation which exceeded that of all reported organic catalysts tested in this system. The process was accompanied by the intensive oxygen consumption and increase in the steady-state concentration of the ascorbyl radical Asc.-. The rate of oxygen consumption (R[OX]) was maximal at the moment of reagent mixing ((R[OX]0) and then reduced over a few minutes until a steady-state level ((R[OX])SS) was achieved. (R[OX])0 was found to be proportional to [UQ][AscH-] without regard to the concentrations of the individual reagents; (R[OX])SS was directly related to [UQ] at a given concentration of AscH-. The difference between (R[OX])0 and (R[OX])SS decreased as [AscH-] decreased. The presence of a lipid phase (sodium dodecylsulphate micelles) only moderately decreased UQ activity as a catalyst of AscH- oxidation. Adding micromolar concentrations of UQ induced the acceleration of EP autoxidation. The capability of UQ to catalyze the oxidation of EP exceeded by approximately 25 times that of adrenochrome, a quinoid product of EP oxidation. These catalytic properties of UQ allowed us to predict its pronounced cytotoxicity, especially in the presence of AscH- and to cells of the sympathetic nervous system which are rich in catecholamines. This possibility was confirmed by experiments with human neuroblastoma cells in culture. The capability of UQ to injure neuroblastoma cell line SK-N-SH exceeded that of well-known neurotoxic agents 6-hydroxydopamine and menadione.

Antineoplastic Agents↗

PubMed1984

Attenuation by antioxidants of Na+/K+ ATPase inhibition by toxic concentrations of isoproterenol in cultured rat myocardial cells.

We have reported previously that toxic concentrations of isoproterenol caused severe alterations in the structural integrity of the sarcolemma and mitochondria found in primary cultures of rat myocardial cells [8, 9]. Mitochondrial injury was observed 1.5 h after exposure to isoproterenol, whereas leakage of intracellular ions and enzymes was observed only after prolonged exposures (greater than 4 h). Ascorbic acid and sodium bisulfite prevented the cytotoxic effects of isoproterenol in our cell culture system. Takeo et al. [13] suggested that adrenochrome (an oxidative metabolite of epinephrine) specifically inhibits the activity of the sodium/potassium ATPase. Other investigators have shown that an indole metabolite of epinephrine inhibited actomyosin ATPase [1, 4]. These inhibitory actions may result from an interaction between the oxidative metabolites and sulfhydryl groups present in the enzyme [13]. Inhibition of the sodium/potassium ATPase is associated with an increase in the intracellular concentration of Na+ and Ca2+ and a decrease in intracellular K+. Changes in the intracellular concentration of these ions are commonly seen in heart cell damage and contractile failure [2]. The present study was designed to determine if isoproterenol, a synthetic catecholamine, inhibits the sodium/potassium ATPase activity in a primary culture system of rat myocardial cells.

Animals↗

PubMed1976

Factors affecting prostaglandin synthesis by rat skin microsomes.

Prostaglandin synthesis by rat skin was measured by a radiochemical method and the adrenochrome spectrophotometric method. About 70% of the total enzyme activity was located in the microsomal fraction. Incubation with (1-14C) arachidonic acid resulted in the formation of prostaglandins F2alpha, E2 and D2. The biosynthesis of these 3 prostaglandins was stimulated by reduced glutathione and hydroquinone, and was markedly dependent on pH. A number of non-steroid anti-inflammatory drugs produced a dose related inhibition of prostaglandin biosynthesis. Five potent corticosteroid anti-inflammatory agents previously found to be inhibitory when a skin homogenate was used did not inhibit prostaglandin synthesis by the microsomal fraction.

Animals↗

PubMed1997

Oxidative reactions and schizophrenia: a review-discussion.

Now that definitive direct evidence has been obtained that oxidized metabolites of catecholamines-aminochrome (derived from dopamine) and related compounds-occur in the human brain the question this paper explores is what is their function there, if any. They are precursors of neuromelanin and are formed inter alia by co-oxidation by prostaglandin H synthase during the synthesis of prostaglandin H from arachidonic acid. Their further metabolism by NAHPD-cytochrome P450 reductase forms the highly neurotoxic o-semiquinone together with free oxygen radicals. The defenses against these orthoquinones (o-quinones) and o-semiquinones (which include reduction, O-methylation, 5-cysteinylization, glutathione conjugation, conversion to the o-hydroquinone, and neuromelanin formation), and their possible status in schizophrenia, are reviewed. This system is closely linked with glutamate neurotoxicity because glutamate receptors activate PGH synthase and because dopamine toxicity is mediated by these o-quinones acting on NMDA receptors. Interactions between glutamate and dopamine neurotoxicity are explored, including a possible role for the redox properties of catecholamines. The hypothesis is presented that some of the demonstrated cellular damage in the schizophrenic brain may be mediated by catecholamine o-quinones. The significance of the evidence from previous studies carried out 40 years ago, that a closely related catecholamine o-quinone-adrenochrome-has psychotomimetic properties in humans and behavior disrupting properties in animals, is reviewed in the light of these recent findings.

Brain Chemistry↗

PubMed2005

Catecholamine-induced release of nitric oxide from N-nitrosotryptophan derivatives: a non-enzymatic method for catecholamine oxidation.

In recent years, interest in the physiological functions of S-nitrosothiols has strongly increased owing to the potential of these compounds to release nitric oxide. In contrast, little is known about similar functions of N-nitrosated (N-terminal-blocked) tryptophan derivatives, which can be also formed at physiological pH. Utilizing N-acetyl-N-nitrosotryptophan (NANT) and N-nitrosomelatonin (NOMela) as model compounds, we have studied their reaction with catechol and catecholamines such as epinephrine and dopamine. In these reactions, NANT was quantitatively converted to N-acetyltryptophan (NAT), and nitric oxide was identified as a volatile product. During this process, ortho-semiquinone-type radical anions deriving from catechol and dopamine, were detected by ESR spectrometry. The catechol radical concentration was about eight times higher under normoxia than under hypoxia and a similar relationship was found for the decay rates of NANT under these conditions. An epinephrine-derived oxidation product, namely adrenochrome, but not a catechol-derived one, was identified. These observations strongly indicate that N-nitrosotryptophan derivatives transfer their nitroso-function to an oxygen atom of the catecholamines, and that the so-formed intermediary aryl nitrite may decompose homolytically with release of nitric oxide, in addition to a competing hydrolysis reaction to yield nitrite and the corresponding catechol. These conclusions were supported by quantum chemical calculations performed at the CBS-QB3 level of theory. Since nitric oxide is non-enzymatically released from N-nitrosotryptophan derivatives on reaction with catecholamines, there might be a possibility for the development of epinephrine-antagonizing drugs in illnesses like hypertension and pheochromocytoma.

Catecholamines↗

PubMed2001

Neuronal nitric oxide synthase generates superoxide from the oxygenase domain.

When l-arginine is depleted, neuronal nitric oxide synthase (nNOS) has been reported to generate superoxide. A flavoprotein module construct of nNOS has been demonstrated to be sufficient for superoxide production. In contrast, nNOS was reported not to be involved in superoxide formation, because such formation occurred with a mixture of the boiled enzyme and redox-active cofactors. We aimed to resolve these controversial issues by examining superoxide generation, without the addition of redox-active cofactors, by recombinant wild-type nNOS and by C415A-nNOS, which has a mutation in the haem proximal site. In a superoxide-sensitive adrenochrome assay, the initial lag period of C415A-nNOS was increased 2-fold compared with that of native nNOS. With ESR using the spin trap 5,5-dimethyl-1-pyrroline-N-oxide, prominent signals of the superoxide adduct were obtained with wild-type nNOS, whereas an enzyme preparation boiled for 5 min did not produce superoxide. Higher concentrations of NaCN (10 mM) decreased superoxide formation by 63%. Although the activity of the reductase domain was intact, superoxide generation from C415A-nNOS was decreased markedly, to only 10% of that of the wild-type enzyme. These results demonstrate that nNOS truly catalyses superoxide formation, that this involves the oxygenase domain, and that full-length nNOS hinders the reductase domain from producing superoxide.

Animals↗

PubMed1977

Relationship between the reduction of oxygen, artificial acceptors and cytochrome P-450 by NADPH--cytochrome c reductase.

The interaction of NADPH--cytochrome c reductase with oxygen, artificial acceptors and cytochrome P-450 was studied. The generation of superoxide anion radicals (O2-.) from the oxidation of adrenaline to adrenochrome catalysed by NADPH--cytochrome c reductase proceeds independently of the interaction of the enzyme with the artificial anaerobic acceptors cytochrome c or 2,6-dichlorophenol-indophenol. Propyl 3,4,5-trihydroxybenzoate inhibited competitively the adrenaline oxidation by isolated NADPH--cytochrome c reductase (Ki 3.2--4.7 micrometer) and inhibited non-competitively the cytochrome c reduction (Ki 92--109 micrometer). In contrast with the process of electron transfer to cytochrome c, the rate of reduction of cytochrome P-450 and the rate of oxidation of adrenaline in liver microsomal fraction are correlated. Hexobarbital increases the Vmax. of adrenaline oxidation without affecting the Km value, whereas metyrapone, a metabolic inhibitor decreases Vmax. without affecting the Km. From the results obtained, some conclusions about NADPH--cytochrome c reductase function were made.

2,6-Dichloroindophenol↗

PubMed1991

Specificity of dopachrome tautomerase and inhibition by carboxylated indoles. Considerations on the enzyme active site.

Dopachrome tautomerase (EC 5.3.2.3) catalyses the tautomerization of dopachrome to 5,6-dihydroxyindole-2-carboxylic acid (DHICA) within the melanin-formation pathway. We have analysed a series of substrate analogues and related compounds as possible substrates and inhibitors of tautomerization. The enzyme appears to be highly specific since D-dopachrome, alpha-methyldopachrome, dopaminochrome, adrenochrome methyl ether and deoxyadrenochrome are not substrates. Conversely, dopachrome tautomerase catalyses the tautomerization of dopachrome methyl ester, suggesting that a carboxy group, either free or as a methyl ester, is essential for enzyme recognition. No inhibition of dopachrome tautomerization was observed in the presence of either semiquinonic compounds, such as tropolone and L-mimosine, or pyrrole-2-carboxylic acid and unsubstituted indole. However, a number of indole derivatives, including DHICA, the product of dopachrome tautomerization, and the analogues 5-hydroxyindole-2-carboxylic and indole-2-carboxylic acid were able to inhibit the enzyme. Furthermore, indoles with a side chain at position 3 of the ring and containing a carboxylic group at the gamma-position of this chain, such as L-tryptophan or indole-3-propionic acid, are stronger inhibitors of the enzyme. Indole-3-carboxylic acid, indole-3-acetic acid and indole-3-butyric acid are very weak inhibitors, showing that the carboxylic group needs to be located at an optimal distance from the indole ring to mimic the carboxylic group at position 2 on the authentic substrate.

Ammonium Sulfate↗

PubMed1994

A new dopachrome-rearranging enzyme from the ejected ink of the cuttlefish Sepia officinalis.

A melanogenic enzyme catalysing the rearrangement of dopachrome has been identified in the ejected ink of the cuttlefish Sepia officinalis. This enzyme occurs as a heat-labile protein which co-migrates with tyrosinase under a variety of chromatographic and electrophoretic conditions. On SDS/PAGE it shows like a single band with an approx. molecular mass of 85 kDa. The enzyme possesses high substrate specificity, acting on L-dopachrome (Km = 1 mM at pH 6.8) and on L-alpha-methyl-dopachrome, but not on D-dopachrome, L-dopachrome methyl ester, dopaminochrome and adrenochrome. Significant inhibition of the catalytic activity was observed with tropolone and L-mimosine. H.p.1.c. analysis of the enzyme-catalysed rearrangement of L-dopachrome revealed the quantitative formation of the decarboxylated product, 5,6-dihydroxyindole. These results point to marked differences between melanogenesis in cephalopod pigment cells and in melanocytes, which may have important implications in relation to the use of sepiomelanin as a model for studies of mammalian melanins.

Animals↗

PubMed1998

Mammalian thioredoxin reductase is irreversibly inhibited by dinitrohalobenzenes by alkylation of both the redox active selenocysteine and its neighboring cysteine residue.

The immunostimulatory dinitrohalobenzene compound 1-chloro-2, 4-dinitrobenzene (DNCB) irreversibly inhibits mammalian thioredoxin reductase (TrxR) in the presence of NADPH, inducing an NADPH oxidase activity in the modified enzyme (Arnér, E. S. J., Björnstedt, M., and Holmgren, A. (1995) J. Biol. Chem. 270, 3479-3482). Here we have further analyzed the reactivity with the enzyme of DNCB and analogues with varying immunomodulatory properties. We have also identified the reactive residues in bovine thioredoxin reductase, recently discovered to be a selenoprotein. We found that 4-vinylpyridine competed with DNCB for inactivation of TrxR, with DNCB being about 10 times more efficient, and only alkylation with DNCB but not with 4-vinylpyridine induced an NADPH oxidase activity. A number of nonsensitizing DNCB analogues neither inactivated the enzyme nor induced any NADPH oxidase activity. The NADPH oxidase activity of TrxR induced by dinitrohalobenzenes generated superoxide, as detected by reaction with epinephrine (the adrenochrome method). Addition of superoxide dismutase quenched this reaction and also stimulated the NADPH oxidase activity. By peptide analysis using mass spectrometry and Edman degradation, both the cysteine and the selenocysteine in the conserved carboxyl-terminal sequence Gly-Cys-Sec-Gly (where Sec indicates selenocysteine) were determined to be dinitrophenyl-alkylated upon incubation of native TrxR with NADPH and DNCB. A model for the interaction between TrxR and dinitrohalobenzenes is proposed, involving a functional FAD in the alkylated TrxR generating an anion nitroradical in a dinitrophenyl group, which in turn reacts with oxygen to generate superoxide. Production of reactive oxygen species and inhibited reduction of thioredoxin by the modified thioredoxin reductase after reaction with dinitrohalobenzenes may play a major role in the inflammatory reactions provoked by these compounds.

Alkylation↗