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Biomedical subjects

G J Quinlan

Publications and source records attributed to G J Quinlan.

At least 55 records · Page 3Linked to original sources
PubMed1994

Plasma 4-hydroxy-2-nonenal levels during cardiopulmonary bypass, and their relationship to the iron-loading of transferrin.

4-Hydroxy-2-nonenal (HNE) an aldehydic peroxidation produce of n-6 fatty acids, is formed predominantly in model systems when redox active transition metal ions, particularly iron, are present. During cardiopulmonary bypass surgery blood is circulated and oxygenated extracorporeally, and periods of tissue ischaemia-reoxygenation are introduced. Both events cause oxidative stress with the generation of reactive forms of oxygen leading to lipid peroxidation. During bypass iron is released often saturating plasma transferrin, and resulting in the appearance of chelatable iron in the plasma. Because such forms of iron can promote HNE formation in vitro, we have studied 12 bypass patients, 5 of whom had plasma iron-overload. Our results show a greater percentage increase in HNE formation during bypass when the plasma transferrin is iron-overloaded compared with matched controls not showing iron-overload.

Adult↗
PubMed1994

Primary plasma antioxidants in adult respiratory distress syndrome patients: changes in iron-oxidizing, iron-binding, and free radical-scavenging proteins.

Ten adult patients (three male, age range, 15 to 67 years) with established ARDS were studied for serial changes in the proteinaceous antioxidant activities of their plasma. All had LISs in excess of 2.5 on admission to the study. Blood samples were taken as soon as possible after the diagnosis of ARDS, and from 10 patients at risk of developing ARDS. These were compared with healthy control subjects. Deoxyribose, phospholipids, and DNA were used as markers of damage in reactions generating inorganic and organic oxygen radicals and an oxo-iron species. The ability of plasma to inhibit such damage was expressed as antioxidant activity. This study does not address the clinical problem of why certain "at risk" patients develop ARDS, but rather the question of why some patients with established ARDS are better able than others to survive the disease. ARDS patients had transferrin levels that were significantly lower (1.76 +/- 0.13 gm/L) than those of normal controls (2.91 +/- 0.12 gm/L, p < 0.001), which decreased the ability of their plasma to protect phospholipid membranes and DNA against iron-stimulated free radical damage. The iron-oxidizing antioxidant properties of plasma were mainly dependent on the protein ceruloplasmin, concentrations of which were significantly higher in ARDS patients (0.387 +/- 0.04 gm/L) than in healthy controls (0.265 +/- 0.03 gm/L, p = < 0.05) or patients at risk of ARDS (0.24 +/- 0.04 gm/L, p = < 0.05). The iron-oxidizing (ferroxidase) antioxidant activities of plasma from ARDS patients, however, were similar to those of both control groups. Measurement of plasma ferroxidase activities confirmed that although more ceruloplasmin was present in the plasma of ARDS patients, enzyme activities were comparable to those of both control groups, which was suggestive of a loss of ceruloplasmin ferroxidase activity. Scavenging and radical-stimulating properties of plasma (devoid of iron-binding and iron-oxidizing properties) was partly dependent on protein thiol groups, which were lower in ARDS patients and in patients at risk of developing ARDS. Serial sample analysis revealed that ARDS patients showed substantial daily variations in biochemical parameters, implying that single time-point sampling may be unsuitable when studying these patients.

Adolescent↗
PubMed1993

Chelatable iron and copper can be released from extracorporeally circulated blood during cardiopulmonary bypass.

During cardiopulmonary bypass surgery blood is extracorporeally oxygenated and circulated before returning to the systemic arterial circulation. Blood undergoing extracorporeal dilution and circulation is exposed to non-physiological surfaces, which cause the activation of several regulatory cascades. Cells are also subjected to damaging shear stresses. Under such conditions neutrophils can be 'activated' to release reactive oxygen intermediates such as O2- and H2O2, and other cells can release proteolytic enzymes and metalloproteins. Collectively, these events can result in the release of micromolar quantities of redox active iron and copper. Bleomycin-detectable iron and phenanthroline-detectable copper were found in two out of four mock bypass experiments. However, there was no correlation between the presence of chelatable iron and copper and the activation of neutrophils measured as elastase.

Bleomycin↗
PubMed1993

Antioxidant protection against organic and inorganic oxygen radicals by normal human plasma: the important primary role for iron-binding and iron-oxidising proteins.

Normal human plasma contains numerous high and low molecular mass redox active molecules that are able to react rapidly with organic and inorganic oxygen radicals. The ability of such plasma molecules to substantially inhibit, or delay, free radical mediated oxidation of added substrates has led to their classification as important biological antioxidants. Using phospholipids to detect organic oxygen radicals, and deoxyribose to detect inorganic oxygen radicals, we here show that the primary antioxidants of normal human plasma reside mainly in two plasma proteins representing no more than 4% of the total proteins present. The iron-binding properties of transferrin and the iron-oxidising properties of caeruloplasmin, at a reaction dilution of 1:50, offer considerable protection against organic and inorganic oxygen radicals generated by iron and ascorbate. Plasma thiol group-containing molecules, at concentrations well below those that would be required to compete with the detector molecule (based on known second order rate constants for reaction with hydroxyl radicals) inhibited damage to deoxyribose, but stimulated damage to phospholipids.

Antioxidants↗
PubMed1992

Antioxidant protection against organic and inorganic oxygen radicals by normal human plasma: the important primary role for iron-binding and iron-oxidising proteins.

Normal human plasma contains numerous high- and low-molecular-mass redox-active molecules that are able to react rapidly with organic and inorganic oxygen radicals. The ability of such plasma molecules to substantially inhibit, or delay, free-radical mediated oxidation of added substrates has led to their classification as important biological antioxidants. Using phospholipids to detect organic oxygen radicals and deoxyribose to detect inorganic oxygen radicals, we here show that the primary antioxidants of normal human plasma reside mainly in two plasma proteins representing no more than 4% of the total proteins present. The iron-binding properties of transferrin and the iron-oxidising properties of caeruloplasmin, at a reaction dilution of 1:50, offer considerable protection against organic and inorganic oxygen radicals generated by iron and ascorbate. Plasma thiol-group-containing molecules, at concentrations well below those that would be required to compete with the detector molecule (based on known second-order rate constants for reaction with hydroxyl radicals) inhibited damage to deoxyribose, but stimulated damage to phospholipids.

Antioxidants↗
PubMed1992

Vanadium and copper in clinical solutions of albumin and their potential to damage protein structure.

Solutions of albumin, for injectable use in humans, are shown to contain the transition metals vanadium, copper, and iron. Variation in the concentration of these metal ions among products from six different manufacturers suggests that problems of metal contamination arise through manufacturing processes. Vanadium concentrations correlated with the loss of tryptophan residues in albumin, whereas copper concentrations correlated with loss of thiol groups and tryptophan residues. Incubation of vanadate and cupric salts with the thiol group-containing molecules cysteine and glutathione resulted in reduction of the metal ions to lower oxidation states. Reduced forms of vanadium and copper were able to transfer electrons to molecular oxygen and produce highly reactive and damaging intermediates of oxygen, such as the hydroxyl radical.

Albumins↗
PubMed1992

Aluminium-adjuvanted vaccines transiently increase aluminium levels in murine brain tissue.

Aluminium is widely used as an adjuvant in human vaccines, and children can often receive up to 3.75 mg of parenteral aluminium during the first six months of life. We show that intraperitoneal injection of aluminium adsorbed vaccines into mice causes a transient rise in brain tissue aluminium levels peaking around the second and third day after injection. This rise is not seen in the saline control group of animals or with vaccine not containing aluminium. It is likely that aluminium is transported to the brain by the iron-binding protein transferrin and enters the brain via specific transferrin receptors.

Adjuvants, Immunologic↗
PubMed1991

DNA base damage by beta-lactam, tetracycline, bacitracin and rifamycin antibacterial antibiotics.

Several antibacterial antibiotics have been shown to participate with transition metal ions in chemical reactions leading to the formation of reactive oxygen species. An important host defence mechanism for dealing with invading bacteria involves the production of reactive oxygen species, such as superoxide, hydrogen peroxide and hypochlorous acid, by phagocytic cells. The production of reactive oxygens by redox cycling antibacterial antibiotics has led us to suggest that a 'phagomimetic' contribution may also be made in vivo. Here we show that four structurally different antibacterial antibiotics, in the presence of added copper salt, bring about oxidative modification to bases in DNA detected using gas chromatography-mass spectrometry. The drug most damaging to DNA was rifamycin SV which was more active than a reference mixture of hydrogen peroxide and ascorbic acid.

Bacitracin↗
PubMed1989

The mechanism of initiation of lipid peroxidation. Evidence against a requirement for an iron(II)-iron(III) complex.

When Fe2+ ions are added to rat-liver microsomes, lipid peroxidation begins after a short lag period. Fe2+-dependent peroxidation in the first few minutes of the incubation can be increased by adding Fe3+, ascorbic acid or Pb2+ ions; these stimulations are not additive. By contrast, Pb2+ ions inhibit peroxidation of microsomes in the presence of Fe3+/ascorbate or Fe3+-ADP/NADPH. In liposomes made from ox-brain phospholipids, Fe2+-dependent peroxidation is stimulated slightly by Fe3+, but much more so by ascorbic acid, Al3+ or Pb2+; these stimulations are not additive. Liposomal peroxidation in the presence of Fe3+/ascorbate is inhibited by Pb2+ or Al3+. These results argue against the participation of an Fe2+-Fe3+-O2 complex, or a critical 1:1 ratio of Fe2+ to Fe3+, in the initiation of lipid peroxidation in liposomes and rat-liver microsomes.

Aluminum↗
PubMed1989

Bacitracin and a bacitracin-zinc complex damage DNA and carbohydrate in the presence of iron and copper salts.

The antibiotic bacitracin binds metal ions such as zinc, copper and iron, and is often prepared for clinical and veterinary use as a zinc complex to enhance stability. Here, we show that bacitracin and its zinc complex are able to reduce copper and iron salts with the formation of hydrogen peroxide. This results in damage to the bacitracin molecule and the release of some oxidising radicals into free solution that attack detector molecules such as deoxyribose and DNA. Damage to deoxyribose and DNA can be detected by the formation of thiobarbituric acid-reactive material and this damage can be protected against by the addition of scavengers of the hydroxyl radical implicating the OH radical in the degradation observed.

Bacitracin↗
PubMed1988

Action of lead(II) and aluminium (III) ions on iron-stimulated lipid peroxidation in liposomes, erythrocytes and rat liver microsomal fractions.

Lead (Pb2+) ions accelerate the lipid peroxidation observed when Fe2+ ions are added to phospholipid liposomes at pH 5.5 or pH 7.4, although Pb2+ ions alone do not induce any peroxidation. Similarly, aluminium (Al3+) ions increase Fe2+-dependent liposomal peroxidation at pH 5.5. Both Pb2+ and Al3+ accelerate the peroxidation of erythrocytes induced by high concentrations of H2O2 in the presence of azide, and they also increase the peroxidation that occurs when Fe2+ or Fe2+-ADP is added to rat liver microsomes at pH 7.4. It is proposed that increased lipid peroxidation may contribute to the toxic actions of Pb2+ in humans.

Aluminum↗
PubMed1988

Hydroxyl radical generation by the tetracycline antibiotics with free radical damage to DNA, lipids and carbohydrate in the presence of iron and copper salts.

Tetracycline antibiotics caused the degradation of carbohydrate in the presence of a ferric salt at pH 7.4. This degradation appeared to involve hydroxyl radicals since the damage was substantially reduced by the presence of catalase, superoxide dismutase, scavengers of the hydroxyl radical and metal chelators. Similarly, the tetracycline antibiotics in the presence of a ferric salt greatly stimulated the peroxidation of liposomal membranes. This damage, which did not implicate the hydroxyl radical, was significantly reduced by the addition of chain-breaking antioxidants and metal chelators. Only copper salts in the presence of tetracycline antibiotics, however, caused substantial damage to linear duplex DNA. Studies with inhibitors suggested that damage to DNA did involve hydroxyl radicals.

Animals↗
PubMed1988

Oxidative damage to DNA and deoxyribose by beta-lactam antibiotics in the presence of iron and copper salts.

beta-lactam antibiotics in the presence of certain metal ions damage deoxyribose and DNA with the release of thiobarbituric acid-reactive material. This damage can be substantially prevented by catalase, metal chelators and some scavengers of the hydroxyl radical. Ferric salts in the presence of certain beta-lactam antibiotics were effective in degrading deoxyribose but they did not appear to damage DNA. In contrast copper salts and beta-lactam antibiotics were extremely effective in damaging both DNA and deoxyribose.

Anti-Bacterial Agents↗
PubMed1987

Oxygen radical damage to DNA by rifamycin SV and copper ions.

The hydroquinone moiety of the antibiotic rifamycin SV reacts with molecular oxygen to form reduced oxygen intermediates such as superoxide (O2-.) and hydrogen peroxide (H2O2). The antibiotic semiquinone is also formed. Rifamycin SV in the presence of iron and copper salts can lead to the formation of the highly reactive hydroxyl radical (OH) which degrades the sugar deoxyribose. This damage is substantially inhibited by the enzyme catalase and scavengers of the hydroxyl radical such as formate, mannitol and thiourea. When linear duplex DNA is substituted for deoxyribose only rifamycin SV and copper ions substantially degrade DNA with release from the DNA molecule of thiobarbituric acid-reactive products. Damage to DNA by rifamycin and copper ions is significantly inhibited by catalase but poorly inhibited by scavengers of the hydroxyl radical consistent with a site-specific radical reaction of the DNA molecule. Several biological properties of rifamycin SV are known to resemble those of the metal chelating agent 1,10-phenanthroline. Here, we show that similarities extend to an unusual chemical property whereby thiobarbituric acid-reactive material is released from DNA in the presence of a copper salt.

Copper↗
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

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

Catalase enhances damage to DNA by bleomycin-iron(II): the role of hydroxyl radicals.

Bleomycin degrades DNA under aerobic conditions when a ferrous salt is added. This reaction is enhanced by catalase and certain hydroxyl radical scavengers but inhibited by the addition of hydrogen peroxide. A ferricbleomycin complex is, however, stimulated by addition of hydrogen peroxide. These findings suggest that catalase removes hydrogen peroxide and in so doing prevents loss of ferrous ions and formation of hydroxyl radicals (OH.) by a Fenton-type reaction. It further suggests that OH. radicals, when formed, are more involved in the inactivation of bleomycin than in the release of thiobarbituric acid reactive material from DNA.

Animals↗