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Biomedical subjects

J M Gutteridge

Publications and source records attributed to J M Gutteridge.

At least 127 records · Page 7Linked to original sources
PubMed1986

Copper + zinc and manganese superoxide dismutases inhibit deoxyribose degradation by the superoxide-driven Fenton reaction at two different stages. Implications for the redox states of copper and manganese.

When OH. radicals are formed in a superoxide-driven Fenton reaction, in which O2.- is generated enzymically, deoxyribose degradation is effectively inhibited by CuZn- and Mn-superoxide dismutases. The products of this reaction are H2O2 and a Fe3+-EDTA chelate. The mixing of H2O2 and a Fe3+-EDTA chelate also generates OH. radicals able to degrade deoxyribose with the release of thiobarbituric acid-reactive material. This reaction too is inhibited by CuZn- and Mn-superoxide dismutases, suggesting that most of the OH. is formed by a non-enzymic O2.--dependent reduction of the Fe3+-EDTA chelate. Since the reaction between the Fe3+-EDTA chelate and H2O2 leads to a superoxide dismutase-inhibitable formation of OH. radicals, it could suggest a much wider protective role for the superoxide dismutase enzymes in biological systems. Urate produced during the reaction of xanthine oxidase and hypoxanthine limits deoxyribose degradation as well as the effectiveness of the superoxide dismutase enzymes to inhibit damage to deoxyribose by H2O2 and the Fe3+-EDTA chelate. Some of this damage may result from an O2.--independent pathway to OH. formation in which urate reduces the ferric complex.

Cations, Divalent↗
PubMed1986

Antioxidant properties of the proteins caeruloplasmin, albumin and transferrin. A study of their activity in serum and synovial fluid from patients with rheumatoid arthritis.

Patients with rheumatoid arthritis have altered protein patterns in their serum and synovial fluid which influences the antioxidant activity of these fluids. Rheumatoid serum has a higher antioxidant activity than control serum when ferrous and ferric ions stimulate membrane damage. The raised levels of caeruloplasmin and the lower iron saturation of transferrin contribute to these differences. When membrane damage is stimulated by a copper salt, rheumatoid serum does not show an increased antioxidant protection and has probably a lower protective activity than control serum. Attempts to damage caeruloplasmin and transferrin with oxygen radicals were unsuccessful. However, prolonged incubations with trypsin reduced the iron-binding capacity of transferrin and decreased the ferroxidase and antioxidant properties of caeruloplasmin. Copper was released from caeruloplasmin under these conditions.

Antioxidants↗
PubMed1986

Susceptibility of tamarin (Saguinus labiatus) red blood cell membrane lipids to oxidative stress: implications for wasting marmoset syndrome.

Captive Callitrichids frequently suffer a fatal wasting disease, wasting marmoset syndrome (WMS), of unexplained cause. This paper describes studies on the erythrocytes from animals in a breeding colony of tamarins (Saguinus labiatus), in which deaths from anaemia and wasting were occurring, to seek evidence for biochemical changes which could lead to oxidative damage and premature cell lysis. In only one animal of 33 studied did the red blood cell lipids show an increased susceptibility to oxidative damage. This animal, with some degree of certainty, could be diagnosed as having WMS. It was concluded that evidence for a primary deficiency of antioxidants as a cause of unexplained deaths, or WMS, in the colony could not at present be substantiated.

Animals↗
PubMed1986

Iron complexes and their reactivity in the bleomycin assay for radical-promoting loosely-bound iron.

The sensitivity of the bleomycin assay for loosely-bound iron depends on the concentration of bleomycin and ascorbic acid and the pH of the reaction. The non-haem-iron proteins transferrin, conalbumin and ferritin release iron at an acid pH value, whereas the haem-iron proteins release iron more readily at an alkaline pH. In addition, haem proteins are liable to release iron when peroxides are present. Organic peroxides and hydrogen peroxide can be produced during the bleomycin reaction leading to iron release from haem proteins. However, this can be prevented from reacting with bleomycin by adding zinc ions to the reaction following addition of the sample. Iron already bound to bleomycin is not displaced by zinc whereas zinc bound to bleomycin is not displaced by iron allowing 'free' and 'released' iron to be discriminated.

Ascorbic Acid↗
PubMed1985

Inhibition of the Fenton reaction by the protein caeruloplasmin and other copper complexes. Assessment of ferroxidase and radical scavenging activities.

The copper-containing protein caeruloplasmin is an important biological extracellular protein. By catalysing the oxidation of ferrous ions to the ferric state (ferroxidase activity) it can inhibit lipid peroxidation and the Fenton reaction. This activity is readily destroyed by heat-denaturation. When a ferric-EDTA complex is added to hydrogen peroxide, OH X radicals are formed in a reaction inhibitable by superoxide dismutase (SOD). This reaction is also inhibited by caeruloplasmin both before and after heat-denaturation, suggesting a non-catalytic scavenging role for the protein. A combination of ferroxidase and radical scavenging activities in fluids containing iron complexes and hydrogen peroxide, but no SOD or catalase, would make caeruloplasmin an important extracellular antioxidant.

Ceruloplasmin↗
PubMed1985

Metal ions and oxygen radical reactions in human inflammatory joint disease.

Activated phagocytic cells produce superoxide (O2-) and hydrogen peroxide (H2O2); their production is important in bacterial killing by neutrophils and has been implicated in tissue damage by activated phagocytes. H2O2 and O2- are poorly reactive in aqueous solution and their damaging actions may be related to formation of more reactive species from them. One such species is hydroxyl radical (OH.), formed from H2O2 in the presence of iron- or copper-ion catalysts. A major determinant of the cytotoxicity of O2- and H2O2 is thus the availability and location of metal-ion catalysts of OH. formation. Hydroxyl radical is an initiator of lipid peroxidation. Iron promoters of OH. production present in vivo include ferritin, and loosely bound iron complexes detectable by the 'bleomycin assay'. The chelating agent Desferal (desferrioxamine B methanesulphonate) prevents iron-dependent formation of OH. and protects against phagocyte-dependent tissue injury in several animal models of human disease. The use of Desferal for human treatment should be approached with caution, because preliminary results upon human rheumatoid patients have revealed side effects. It is proposed that OH. radical is a major damaging agent in the inflamed rheumatoid joint and that its formation is facilitated by the release of iron from transferrin, which can be achieved at the low pH present in the micro-environment created by adherent activated phagocytic cells. It is further proposed that one function of lactoferrin is to protect against iron-dependent radical reactions rather than to act as a catalyst of OH. production.

Arthritis, Rheumatoid↗
PubMed1985

Cobalt(II) ion as a promoter of hydroxyl radical and possible 'crypto-hydroxyl' radical formation under physiological conditions. Differential effects of hydroxyl radical scavengers.

Co(II) ions react with hydrogen peroxide under physiological conditions to form a 'reactive species' that can hydroxylate aromatic compounds (phenol and salicylate) and degrade deoxyribose to thiobarbituric-acid-reactive material. Catalase decreases the formation of this species but superoxide dismutase or low concentrations of ascorbic acid have little effect. EDTA, present in excess over the Co(II), can accelerate deoxyribose degradation and aromatic hydroxylation. In the presence of EDTA, deoxyribose degradation by the reactive species is inhibited competitively by scavengers of the hydroxyl radical (.OH), their effectiveness being related to their second-order rate constants for reaction with .OH. In the absence of EDTA the scavengers inhibit only at much higher concentrations and their order of effectiveness is changed. It is suggested that, in the presence of EDTA, hydroxyl radical is formed 'in free solution' and attacks deoxyribose or an aromatic molecule. In the absence of EDTA, .OH radical is formed in a 'site-specific' manner and is difficult to intercept by .OH scavengers. The relationship of these results to the proposed 'crypto .OH' radical is discussed.

Chemical Phenomena↗
PubMed1985

Free radical damage to deoxyribose by anthracycline, aureolic acid and aminoquinone antitumour antibiotics. An essential requirement for iron, semiquinones and hydrogen peroxide.

Anthracycline, aureolic acid and aminoquinone antitumour antibiotics damage deoxyribose in cell-free systems when reduced in air by the enzyme ferredoxin reductase. Damage to deoxyribose is inhibited by the iron chelator desferrioxamine, the copper-containing protein caeruloplasmin and catalase but not by superoxide dismutase. Scavengers of the hydroxyl radical such as formate, butan-1-ol, ethanol and benzoate do not offer much protection, whereas mannitol and thiourea do. These findings point to a site-specific Fenton reaction in which the drug semiquinones reduce complexed iron and dioxygen leading to the formation of hydrogen peroxide and a ferrous complex.

Antibiotics, Antineoplastic↗
PubMed1985

The behaviour of caeruloplasmin in stored human extracellular fluids in relation to ferroxidase II activity, lipid peroxidation and phenanthroline-detectable copper.

No Cu(II) ion is measurable in human serum or synovial fluid by the phenanthroline assay. On storage of human serum or synovial fluid at 4 degrees C, phenanthroline-detectable copper appears, lipid peroxidation occurs, ferroxidase I activity declines and ferroxidase II activity rises, yet there is no fall in immunologically detectable caeruloplasmin. Storage of body fluids at -20 degrees C or -70 degrees C slows, but does not prevent, these deteriorative changes. It is suggested that the presence of low-molecular-mass Cu(II) ion complexes, ferroxidase II activity, "cytotoxic factors' and "immunosuppressive factors' in body fluids may be, in part or in whole, an artifact of the storage and handling of the fluids. A report [Blake, Blann, Bacon, Farr, Gutteridge & Halliwell (1983) Clin. Sci. 64, 551-553] that the caeruloplasmin present in rheumatoid synovial fluid is deficient in ferroxidase activity is shown to be such an artifact. It is strongly recommended that all such experiments be performed upon freshly taken fluid samples.

Arthritis, Rheumatoid↗
PubMed1985

Aluminium salts accelerate peroxidation of membrane lipids stimulated by iron salts.

Aluminium salts do not themselves stimulate peroxidation of ox-brain phospholipid liposomes, but they greatly accelerate the peroxidation induced by iron(II) salts at acidic pH values. This effect of Al(III) is not seen at pH 7.4, perhaps because Al(III) salts form insoluble complexes at this pH in aqueous solution. Peroxidation of liposomes in the presence of Al(III) and Fe(II) salts is inhibited by the chelating agent desferrioxamine, and by EDTA and diethylenetriaminepentaacetic acid at concentrations greater than those of Fe(II) salt. Aluminium salts slightly stimulate the peroxidation of peroxide-depleted linolenic acid micelles, but they do not accelerate the peroxidation induced by addition of iron(II) salts to the micelles at acidic pH. Aluminium salts accelerate the peroxidation observed when human erythrocytes are treated with hydrogen peroxide at pH 7.4. Desferrioxamine decreases the peroxidation. We suggest that Al(III) ions produce an alteration in membrane structure that facilitates lipid peroxidation, and that the increased formation of fluorescent age pigments in the nervous system of patients exposed to toxic amounts of Al(III) may be related to this phenomenon. The ability of desferal to bind both iron (III) and aluminium(III) salts and to inhibit lipid peroxidation makes it an especially useful chelating agent in the treatment of 'aluminium overload'.

Aluminum↗
PubMed1985

Superoxide dismutase inhibits the superoxide-driven Fenton reaction at two different levels. Implications for a wider protective role.

Superoxide dismutase (SOD) completely inhibits the damage caused by a ferric-EDTA chelate in the presence of a superoxide-generating system. In this reaction superoxide is enzymically dismuted to hydrogen peroxide. Since hydrogen peroxide and a ferric-EDTA chelate are themselves a hydroxyl radical-generating system, it follows that SOD must also protect against damage done by this reaction. The ability of SOD to inhibit damage to deoxyribose caused by hydrogen peroxide and a ferric-EDTA chelate is experimentally demonstrated in this paper.

Chemical Phenomena↗
PubMed1985

Age pigments and free radicals: fluorescent lipid complexes formed by iron- and copper-containing proteins.

Haem and non-haem iron-containing proteins stimulate lipid peroxidation with the formation of fluorescent lipid complexes. This process requires the presence of lipid hydroperoxides which release ferrozine-reactive iron from haem-containing proteins. Stimulation of lipid peroxidation by the released iron is inhibited by the iron chelator desferrioxamine. Copper ions, although more stimulatory towards fluorescent lipid complex formation than iron ions, do not stimulate lipid peroxidation when tightly bound at the active centre of proteins, but are reactive when loosely bound to albumin and histidine.

Animals↗
PubMed1985

Copper and iron complexes catalytic for oxygen radical reactions in sweat from human athletes.

Sweat collected from 'explosive' and 'endurance' athletes immediately after exercise contains low molecular mass complexes of copper detectable by their ability to bind to o-phenanthroline. Concentrations of these copper complexes are much greater in arm sweat than in trunk sweat. The iron content of arm sweat, as determined by the ferrozine method, is also greater than that of trunk sweat. However, much of the iron in trunk sweat exists in a low molecular mass form that can bind to the antibiotic bleomycin, whereas the iron in arm sweat does not exist in this form. The metal complexes in human sweat are capable of stimulating the peroxidation of membrane lipids in the presence of ascorbic acid. The physiological significance of the presence of iron and copper complexes in sweat is discussed.

Anemia↗
PubMed1985

The importance of free radicals and catalytic metal ions in human diseases.

The study of free radical reactions is not an isolated and esoteric branch of science. A knowledge of free radical chemistry and biochemistry is relevant to an understanding of all diseases and the mode of action of all toxins, if only because diseased or damaged tissues undergo radical reactions more readily than do normal tissues. However it does not follow that because radical reactions can be demonstrated, they are important in any particular instance. We hope that the careful techniques needed to assess the biological role of free radicals will become more widely used.

Aging↗
PubMed1985

Doxorubicin-dependent lipid peroxidation at low partial pressures of O2.

Doxorubicin semiquinone, produced by reduction of doxorubicin with xanthine oxidase or ferredoxin reductase, reacted with H2O2 to cause deoxyribose oxidation that was catalysed by sub-micromolar concentrations of complexed iron. Both the mechanism of deoxyribose oxidation and the yield of oxidation products depended on the chelator. With EDTA or diethylenetriamine penta-acetic acid (DTPA), the reactive species behaved like free . OH. However, when ADP or no chelator was present, oxidation of deoxyribose was inhibited by mannitol but not benzoate or formate and was apparently not due to free . OH. Doxorubicin semiquinone and H2O2 caused peroxidation of phospholipid liposomes when ADP or no chelator was present, but not in the presence of EDTA or DTPA. Lipid peroxidation was iron dependent over a 0.1 to 1 microM range and was maximal with a pO2 of approximately 1.5 mm Hg, when the inhibitory effect of O2 on initiation is balanced by its stimulatory effects on propagation. The results imply that H2O2 and the doxorubicin semiquinone at low iron and O2 concentrations are very effective at initiating lipid peroxidation.

Animals↗
PubMed1985

Low-molecular-weight iron complexes and oxygen radical reactions in idiopathic haemochromatosis.

The sera of patients with idiopathic haemochromatosis and iron-overload have been found to contain low-molecular-weight iron complexes detectable in the 'bleomycin assay'. These complexes stimulate both the peroxidation of membrane lipids and the formation of the highly reactive and damaging hydroxyl radical. The iron chelator desferrioxamine interferes with these reactions. We suggest that oxygen radical reactions stimulated by iron salts are important in the pathology of idiopathic haemochromatosis.

Bleomycin↗
PubMed1985

Effect of intravenous iron dextran on rheumatoid synovitis.

Eleven patients with rheumatoid arthritis received a total dose infusion of iron dextran for anaemia. Two of them had anaphylactic reactions and the remaining nine an exacerbation of synovitis. Quantitative infrared thermal imaging was used to assess the extent and distribution of joint involvement resulting from this therapy. In all eight patients examined the 'thermographic index' increased in two or more joint areas, indicating an increase in inflammation. Small joints of the hands were maximally affected, though larger joints when previously inflamed also worsened. Uninflamed joints were rarely affected. The exacerbation of synovitis occurred 24-48 h after completion of the iron dextran infusion and corresponded with a saturating of the serum iron binding capacity. Levels of immune complexes were unaltered, implying normal reticuloendothelial function. In one further patient, reported to have synovial flares when challenged with oral ferrous sulphate, iron dextran was infused at a lower dosage. All previously inflamed joints in this patient worsened 12 h after the infusion was discontinued. Concomitant with this was an increase of lipid peroxidation products in synovial fluid and to a less extent serum. Iron dextran in vitro stimulated lipid peroxidation, but dextran alone had no effect. It is therefore suggested that iron dextran worsens synovial inflammation by promoting lipid peroxidation.

Adult↗