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  1. Article: Molecular mechanisms of cellular injury produced by neurotoxic amino acids that generate reactive oxygen species.

    Metodiewa, D

    Amino acids

    1998  Volume 14, Issue 1-3, Page(s) 181–187

    Abstract: There is now strong experimental evidence that the basic precursors for the synthesis of catechol(amine) and indolamine neurotransmitters, tyrosine and tryptophan can act as generators of ROS (reactive oxygen species): peroxides, superoxide and ... ...

    Abstract There is now strong experimental evidence that the basic precursors for the synthesis of catechol(amine) and indolamine neurotransmitters, tyrosine and tryptophan can act as generators of ROS (reactive oxygen species): peroxides, superoxide and peroxyradicals. The consequences of free radicals formation from precursors during oxidative degradation process, their possible participation in electron transfer/addition reactions and chain processes involving cell antioxidant defense system were presented and discussed. Although the generation of neurotoxic ROS by tyrosine and tryptophan is accepted to occur in the presented model systems, doubts can exist as to the situation in vivo, which may be completely different and remain to be explored. The relevance of the present findings with regard to a variety of neurological diseases cannot be ignored.
    MeSH term(s) Reactive Oxygen Species ; Tryptophan/toxicity ; Tyrosine/toxicity
    Chemical Substances Reactive Oxygen Species ; Tyrosine (42HK56048U) ; Tryptophan (8DUH1N11BX)
    Language English
    Publishing date 1998
    Publishing country Austria
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1121341-3
    ISSN 1438-2199 ; 0939-4451
    ISSN (online) 1438-2199
    ISSN 0939-4451
    DOI 10.1007/bf01345260
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  2. Article: Reactive oxygen species and reactive nitrogen species: relevance to cyto(neuro)toxic events and neurologic disorders. An overview.

    Metodiewa, D / Kośka, C

    Neurotoxicity research

    2003  Volume 1, Issue 3, Page(s) 197–233

    Abstract: Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are formed under physiological conditions in the human body and are removed by cellular antioxidant defense system. During oxidative stress their increased formation leads to tissue damage ...

    Abstract Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are formed under physiological conditions in the human body and are removed by cellular antioxidant defense system. During oxidative stress their increased formation leads to tissue damage and cell death. This process may be especially important in the central nervous system (CNS) which is vulnerable to ROS and RNS damage as the result of the brain high O(2) consumption, high lipid content and the relatively low antioxidant defenses in brain, compared with other tissues. Recently there has been an increased number of reports suggesting the involvement of free radicals and their non-radical derivatives in a variety of pathological events and multistage disorders including neurotoxicity, apoptotic death of neurons and neural disorders: Alzheimer's (AD), Parkinson's disease (PD) and schizophrenia. Taking into consideration the basic molecular chemistry of ROS and RNS, their overall generation and location, in order to control or suppress their action it is essential to understand the fundamental aspects of this problem. In this presentation we review and summarize the basics of all the recently known and important properties, mechanisms, molecular targets, possible involvement in cellular (neural) degeneration and apoptotic death and in pathogenesis of AD, PD and schizophrenia. The aim of this article is to provide an overview of our current knowledge of this problem and to inspire experimental strategies for the evaluation of optimum innovative therapeutic trials. Another purpose of this work is to shed some light on one of the most exciting recent advances in our understanding of the CNS: the realisation that RNS pathway is highly relevant to normal brain metabolism and to neurologic disorders as well. The interactions of RNS and ROS, their interconversions and the ratio of RNS/ROS could be an important neural tissue injury mechanism(s) involved into etiology and pathogenesis of AD, PD and schizophrenia. It might be possible to direct therapeutic efforts at oxidative events in the pathway of neuron degeneration and apoptotic death. From reviewed data, no single substance can be recommended for use in human studies. Some of the recent therapeutic strategies and neuroprotective trials need further development particularly those of antioxidants enhancement. Such an approach should also consider using combinations of radical(s) scavengers rather than a single substance.
    Language English
    Publishing date 2003-02-26
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2036826-4
    ISSN 1476-3524 ; 1029-8428
    ISSN (online) 1476-3524
    ISSN 1029-8428
    DOI 10.1007/BF03033290
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  3. Article: Studies on the metabolic pathway for itatartaric acid format ion by Aspergillus terreus. II. Use of (-)-citramalate, an d citraconate and itaconate by cell-free extracts

    Jakubowska, J / Metodiewa, D

    Acta microbiologica polonica. Series B: Microbiologia applicata. 1974, 6 (2)

    1974  

    Keywords plant physiology ; plant biochemistry
    Language English
    Size p. 51-61.
    Document type Article
    ZDB-ID 221066-6
    ISSN 0567-7823
    ISSN 0567-7823
    Database NAL-Catalogue (AGRICOLA)

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  4. Article: Reactivity of biologically important thiol compounds with superoxide and hydrogen peroxide.

    Winterbourn, C C / Metodiewa, D

    Free radical biology & medicine

    1999  Volume 27, Issue 3-4, Page(s) 322–328

    Abstract: The reactivities of glutathione, cysteine, cysteamine, penicillamine, N-acetylcysteine, dithiothreitol and captopril with superoxide generated from xanthine oxidase and hypoxanthine, and with reagent hydrogen peroxide, have been investigated. Rates of ... ...

    Abstract The reactivities of glutathione, cysteine, cysteamine, penicillamine, N-acetylcysteine, dithiothreitol and captopril with superoxide generated from xanthine oxidase and hypoxanthine, and with reagent hydrogen peroxide, have been investigated. Rates of thiol loss on adding hydrogen peroxide, and superoxide-dependent thiol loss and oxygen uptake were measured. The relative reactivities of the different thiols with both oxidants were inversely related to the pK of the thiol group, such that at pH 7.4, penicillamine was the most reactive. N-acetylcysteine weakly reactive and no reaction was seen with captopril. For hydrogen peroxide, the calculated rate constants for the reaction with the thiolate anion all fell within the range 18-26 M(-1) s(-1). With superoxide, our results are consistent with each thiol reacting via a short chain that consumes oxygen and regenerates superoxide. Only with some of the thiols, was the consumed oxygen recovered as hydrogen peroxide. Reported values for the rate constant for the reaction of thiols with superoxide vary over four orders of magnitude, with the highest being > 10(5) M(-1) s(-1). Due to the complexity of the chain reaction, no study so far has been able to obtain accurate values and we consider the best estimates to be in the 30 to 1000 M(-1) s(-1) range.
    MeSH term(s) Acetylcysteine/metabolism ; Angiotensin-Converting Enzyme Inhibitors/metabolism ; Captopril/metabolism ; Cysteamine/metabolism ; Cysteine/metabolism ; Dithiothreitol/metabolism ; Glutathione/metabolism ; Hydrogen Peroxide/metabolism ; Oxygen Consumption/physiology ; Penicillamine/metabolism ; Reactive Oxygen Species/metabolism ; Sulfhydryl Compounds/metabolism ; Superoxides/metabolism ; Xanthine Oxidase/metabolism
    Chemical Substances Angiotensin-Converting Enzyme Inhibitors ; Reactive Oxygen Species ; Sulfhydryl Compounds ; Superoxides (11062-77-4) ; Cysteamine (5UX2SD1KE2) ; Captopril (9G64RSX1XD) ; Hydrogen Peroxide (BBX060AN9V) ; Xanthine Oxidase (EC 1.17.3.2) ; Glutathione (GAN16C9B8O) ; Penicillamine (GNN1DV99GX) ; Cysteine (K848JZ4886) ; Dithiothreitol (T8ID5YZU6Y) ; Acetylcysteine (WYQ7N0BPYC)
    Language English
    Publishing date 1999-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 807032-5
    ISSN 1873-4596 ; 0891-5849
    ISSN (online) 1873-4596
    ISSN 0891-5849
    DOI 10.1016/s0891-5849(99)00051-9
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  5. Article: The possible role of one-electron reduction of aminochrome in the neurodegenerative process of the dopaminergic system.

    Segura-Aguilar, J / Metodiewa, D / Baez, S

    Neurotoxicity research

    2004  Volume 3, Issue 2, Page(s) 157–165

    Abstract: We present for discussion a possible molecular mechanism explaining the formation of reactive oxygen species involved in the neurodegenerative process of dopaminergic system in Parkinson's disease. This new hypothesis involves one-electron reduction of ... ...

    Abstract We present for discussion a possible molecular mechanism explaining the formation of reactive oxygen species involved in the neurodegenerative process of dopaminergic system in Parkinson's disease. This new hypothesis involves one-electron reduction of aminochrome to o-semiquinone radical, which seems to be the reaction responsible for neurodegenerative process of dopaminergic system. Leukoaminochrome o-semiquinone is extremely reactive with oxygen, which reoxidizes by reducing oxygen to superoxide radicals. Superoxide radicals enzymatically or spontaneously dismutate to dioxygen and hydrogen peroxide which is a precursor of hydroxyl radicals. ESR-experiments have showed that aminochrome o-semiquinone is extremely reactive in the presence of oxygen compared to dopamine o-semiquinone. In addition, the antioxidant enzymes superoxide dismutase and catalase play a prooxidant role by increasing the autoxidation rate and formation of superoxide radicals. One electron reduction of aminochrome to o-semiquinone can be performed by flavoenzymes which use NADPH and NADH as electron donator. The ability of aminochrome o-semiquinone to autoxidize in the presence of oxygen gives rise to a redox cycling process which will continue until oxygen, NADH and/or NADPH are depleted. Depletion of NADPH will prevent glutathione reductase from reducing glutathione, which is one of the main antioxidants in the cell. In addition depletion of NADH will prevent the formation of ATP in the electron transport chain in the mitochondria. Two antioxidants, probably, neuroprotective reactions are also discussed.
    Language English
    Publishing date 2004-01-20
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2036826-4
    ISSN 1476-3524 ; 1029-8428
    ISSN (online) 1476-3524
    ISSN 1029-8428
    DOI 10.1007/BF03033188
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  6. Article: Submolecular adventures of brain tyrosine: what are we searching for now?

    Kochman, A / Kośka, Cz / Metodiewa, D

    Amino acids

    2002  Volume 23, Issue 1-3, Page(s) 95–101

    Abstract: This overview summarizes recent findings on the role of tyrosyl radical (TyrO(*)) in the multitudinous neurochemical systems of brain, and theorizes on the putative role of TyrO(*) in neurological disorders [Parkinson's disease (PD), Alzheimer's disease ( ...

    Abstract This overview summarizes recent findings on the role of tyrosyl radical (TyrO(*)) in the multitudinous neurochemical systems of brain, and theorizes on the putative role of TyrO(*) in neurological disorders [Parkinson's disease (PD), Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS)]. TyrO(*) and tyrosine per se can interact with reactive oxygen species (ROS) and reactive nitrogen species (RNS) via radical mechanisms and chain propagating reactions. The concentration of TyrO(*), ROS and RNS can increase dramatically under conditions of generalized stress: oxidative, nitrative or reductive as well, and this can induce damage directly (by lipid peroxidation) or indirectly (by proteins oxidation and/or nitration), potentially causing apoptotic neuronal cell death or autoschizis. Evidence of lesion-induced neuronal oxidative stress includes the presence of protein peroxides (TyrOOH), DT (o,o'-dityrosine) and 3-NT (3-nitrotyrosine). Mechanistic details of protein- and enzymatic oxidation/nitration in vivo remain unresolved, although recent in vitro data strongly implicate free radical pathways via TyrO(*). Nitration/denitration processes can be pathological, but they also may play: 1). a signal transduction role, because nitration of tyrosine residues through TyrO(*) formation can modulate, as well the phosphorylation (tyrosine kinases activity) and/or tyrosine hydroxylation (tyrosine hydroxylase inactivation), leading to consequent dopamine synthesis failure and increased degradation of target proteins, respectively; 2). a role of "blocker" for radical-radical reactions (scavenging of NO(*), NO(*)(2) and CO(3)(*-) by TyrO(*)); 3). a role of limiting factors for peroxynitrite formation, by lowering O(2)(*-) formation, which is strongly linked to the pathogenesis of neural diseases. It is still not known if tyrosine oxidation/nitration via TyrO(*) formation is 1). a footprint of generalized stress and neuronal disorders, or 2). an important part of O(2)(*-) and NO(*) metabolism, or 3). merely a part of integral processes for maintaining of neuronal homeostasis. The full answer to these questions should be of top research priority, as the problem of increased free radical formation in brain and/or imbalance of the ratios ROS/RNS/TyrO(*) may be all important in defining whether oxidative stress is the critical determinant of tissue and neural cell injury that leads to pathological end-points.
    MeSH term(s) Brain Chemistry ; Dopamine/metabolism ; Free Radicals/metabolism ; Humans ; Molecular Structure ; Neurodegenerative Diseases/metabolism ; Reactive Oxygen Species/metabolism ; Tyrosine/chemistry ; Tyrosine/metabolism
    Chemical Substances Free Radicals ; Reactive Oxygen Species ; Tyrosine (42HK56048U) ; Dopamine (VTD58H1Z2X)
    Language English
    Publishing date 2002
    Publishing country Austria
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1121341-3
    ISSN 1438-2199 ; 0939-4451
    ISSN (online) 1438-2199
    ISSN 0939-4451
    DOI 10.1007/s00726-001-0114-6
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  7. Article: Reaction of superoxide with glutathione and other thiols.

    Winterbourn, C C / Metodiewa, D

    Methods in enzymology

    1995  Volume 251, Page(s) 81–86

    MeSH term(s) Dithiothreitol/chemistry ; Free Radicals ; Glutathione/chemistry ; Indicators and Reagents ; Kinetics ; Oxidation-Reduction ; Sulfhydryl Compounds/chemistry ; Superoxides/chemistry
    Chemical Substances Free Radicals ; Indicators and Reagents ; Sulfhydryl Compounds ; Superoxides (11062-77-4) ; Glutathione (GAN16C9B8O) ; Dithiothreitol (T8ID5YZU6Y)
    Language English
    Publishing date 1995
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 0076-6879
    ISSN 0076-6879
    DOI 10.1016/0076-6879(95)51112-1
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  8. Article: Antioxidant properties of newly synthesized N-propargylamine derivatives of nitroxyl: a comparison with deprenyl.

    Kochman, Agata / Skolimowski, Janusz / Gebicka, Lidia / Metodiewa, Diana

    Polish journal of pharmacology

    2003  Volume 55, Issue 3, Page(s) 389–400

    Abstract: In our search for novel, low-toxic, cell-penetrable and neuroprotective antioxidants, we have designed a number of novel N-propargylamine derivatives of nitroxyl, named "JSAKs". The reactivity and antioxidative potency of two selected JSAKs and their ... ...

    Abstract In our search for novel, low-toxic, cell-penetrable and neuroprotective antioxidants, we have designed a number of novel N-propargylamine derivatives of nitroxyl, named "JSAKs". The reactivity and antioxidative potency of two selected JSAKs and their parent nitroxyl against reactive oxygen species (ROS) were examined in vitro, in a cell-free gamma-radiolysis and in model Fenton-type reaction systems and compared with those of deprenyl, the investigated member of adjunct therapies in clinical neurology. The efficiency of JSAKs to suppress the oxidative degradation of a model target (deoxyribose), deprenyl and dopamine, caused by hydroxyl radical (*OH) was also investigated. The data demonstrated that the novel compounds, JSAKs, can act as promising antioxidants and protectors of targets against ROS toxicity, thus, providing a sound chemical basis for further comparative investigations of their activity in vivo. The findings were discussed from a mechanistic point of view as well as in terms of the structure-dependent, comprehensive properties of JSAKs as dual-function compounds: antioxidants and anti-apoptotic propargylamines. The novel class of N-propargylamine nitroxyls, JSAKs, may have potential implications for the experimental therapies of Parkinson's disease, where ROS mediate deleterious effects, because these compounds have an ability to either block or reduce the progression of neurotoxic cascade of brain damage.
    MeSH term(s) Antioxidants/chemical synthesis ; Antioxidants/chemistry ; Dopamine/chemistry ; Drug Design ; Molecular Structure ; Neuroprotective Agents/chemical synthesis ; Neuroprotective Agents/chemistry ; Nitrogen Oxides/chemical synthesis ; Nitrogen Oxides/chemistry ; Oxidation-Reduction ; Pargyline/analogs & derivatives ; Pargyline/chemical synthesis ; Pargyline/chemistry ; Propylamines/chemical synthesis ; Propylamines/chemistry ; Reactive Oxygen Species/chemistry ; Selegiline/chemistry ; Structure-Activity Relationship
    Chemical Substances Antioxidants ; Neuroprotective Agents ; Nitrogen Oxides ; Propylamines ; Reactive Oxygen Species ; propargylamine (2450-71-7) ; Selegiline (2K1V7GP655) ; Pargyline (9MV14S8G3E) ; nitroxyl (GFQ4MMS07W) ; Dopamine (VTD58H1Z2X)
    Language English
    Publishing date 2003-05
    Publishing country Poland
    Document type Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1160944-8
    ISSN 1230-6002 ; 0301-0244
    ISSN 1230-6002 ; 0301-0244
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  9. Article: Synthesis and antioxidant activity evaluation of novel antiparkinsonian agents, aminoadamantane derivatives of nitroxyl free radical.

    Skolimowski, Janusz / Kochman, Agata / Gebicka, Lidia / Metodiewa, Diana

    Bioorganic & medicinal chemistry

    2003  Volume 11, Issue 16, Page(s) 3529–3539

    Abstract: Two new analogues of the antiparkinsonian drug 1-aminoadamantane: 4-(1-adamantylamino)-2,2,6,6-tetramethylpiperidine-1-oxyl and 4-(1-adamantylammonio)-1-hydroxy-2,2,6,6-tetramethylpiperidinium dihydrochloride have been synthesized. Their antioxidant ... ...

    Abstract Two new analogues of the antiparkinsonian drug 1-aminoadamantane: 4-(1-adamantylamino)-2,2,6,6-tetramethylpiperidine-1-oxyl and 4-(1-adamantylammonio)-1-hydroxy-2,2,6,6-tetramethylpiperidinium dihydrochloride have been synthesized. Their antioxidant activity towards reactive oxygen species (ROS: (z.rad;)OH and O(2)(z.rad;-)) have been evaluated in three test systems. The compound with nitroxide substituent displays higher anti-oxidative capacity than those containing hydroxylamine. The in vivo study of ROS-involving 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-rat model of induced parkinsonism was undertaken to ascertain the neuroprotective ability of the novel synthesized compounds-antioxidants. The data clearly shows that the nitroxide free radical moiety of the molecule is necessary for their neuroprotective action on dopaminergic neurons under the applied conditions of deep oxidative stress caused by the neurotoxin (MPTP). The new synthesized analogues may find application in treatment of parkinsonian syndromes, either to block or to reduce the ROS-mediated neuronal damage and death.
    MeSH term(s) Adamantane/analogs & derivatives ; Adamantane/chemical synthesis ; Adamantane/chemistry ; Adamantane/pharmacology ; Amantadine/chemistry ; Animals ; Antioxidants/chemical synthesis ; Antioxidants/chemistry ; Antioxidants/pharmacology ; Antiparkinson Agents/chemical synthesis ; Antiparkinson Agents/chemistry ; Antiparkinson Agents/pharmacology ; Brain/drug effects ; Brain/metabolism ; Dopamine/metabolism ; Female ; Free Radicals/chemistry ; Immunohistochemistry ; Molecular Structure ; Nitrogen Oxides/chemistry ; Parkinsonian Disorders/chemically induced ; Parkinsonian Disorders/drug therapy ; Piperidines/chemical synthesis ; Piperidines/chemistry ; Piperidines/pharmacology ; Rats ; Rats, Inbred BUF ; Reactive Oxygen Species/metabolism ; Spectrophotometry ; Tyrosine 3-Monooxygenase/metabolism
    Chemical Substances 4-(1-adamantylamino)-2,2,6,6-tetramethylpiperidine-1-oxyl ; 4-(1-adamantylammonio)-1-hydroxy-2,2,6,6-tetramethylpiperidinium ; Antioxidants ; Antiparkinson Agents ; Free Radicals ; Nitrogen Oxides ; Piperidines ; Reactive Oxygen Species ; Amantadine (BF4C9Z1J53) ; Tyrosine 3-Monooxygenase (EC 1.14.16.2) ; nitroxyl (GFQ4MMS07W) ; Adamantane (PJY633525U) ; Dopamine (VTD58H1Z2X)
    Language English
    Publishing date 2003-05-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1161284-8
    ISSN 1464-3391 ; 0968-0896
    ISSN (online) 1464-3391
    ISSN 0968-0896
    DOI 10.1016/s0968-0896(03)00299-2
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  10. Article: The reaction of superoxide with reduced glutathione.

    Winterbourn, C C / Metodiewa, D

    Archives of biochemistry and biophysics

    1994  Volume 314, Issue 2, Page(s) 284–290

    Abstract: Superoxide, generated by a xanthine oxidase/hypoxanthine system, reacts with reduced glutathione (GSH) to cause an increase in oxygen consumption and oxidized glutathione (GSSG) formation, both of which are fully inhibited by superoxide dismutase. In ... ...

    Abstract Superoxide, generated by a xanthine oxidase/hypoxanthine system, reacts with reduced glutathione (GSH) to cause an increase in oxygen consumption and oxidized glutathione (GSSG) formation, both of which are fully inhibited by superoxide dismutase. In this study we have shown that little, if any, of the additional oxygen consumed is converted to hydrogen peroxide. We have confirmed that approximately 90% of the GSH is oxidized to GSSG, the remainder being converted to the sulfonic acid. Approximately 1.2 mol of GSSG was formed for each additional mole of oxygen consumed in the presence of GSH. The efficiency of the reaction increased with increasing GSH concentration (1-8 mM), pH, and pO2 and with decreasing superoxide generation rate. The results are consistent with a superoxide-dependent chain that does not produce hydrogen peroxide and that is terminated primarily by superoxide dismutation. We propose that this occurs via an initial reaction of superoxide with GSH to produce a sulfinyl radical rather than hydrogen transfer to give the thiyl radical. Our data suggest a rate constant for the superoxide/GSH reaction in the 10(2)-10(3) M-1s-1 range. GSH at the millimolar concentrations found intracellular should react with superoxide, but because superoxide is regenerated, it will not be an effective scavenger. Physiologically, superoxide dismutase is required to prevent chain oxidation of GSH.
    MeSH term(s) Catalase/metabolism ; Glutathione/analogs & derivatives ; Glutathione/chemistry ; Glutathione/pharmacology ; Glutathione Disulfide ; Kinetics ; Mathematics ; Oxygen Consumption ; Superoxide Dismutase/metabolism ; Superoxides/chemistry ; Xanthine ; Xanthine Oxidase/metabolism ; Xanthines/metabolism
    Chemical Substances Xanthines ; Superoxides (11062-77-4) ; Xanthine (1AVZ07U9S7) ; Catalase (EC 1.11.1.6) ; Superoxide Dismutase (EC 1.15.1.1) ; Xanthine Oxidase (EC 1.17.3.2) ; Glutathione (GAN16C9B8O) ; Glutathione Disulfide (ULW86O013H)
    Language English
    Publishing date 1994-11-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 523-x
    ISSN 1096-0384 ; 0003-9861
    ISSN (online) 1096-0384
    ISSN 0003-9861
    DOI 10.1006/abbi.1994.1444
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