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Biomedical subjects

J M Gutteridge

Publications and source records attributed to J M Gutteridge.

At least 91 records · Page 5Linked to original sources
PubMed1991

Reduction of low molecular mass iron by reducing molecules present in plasma and the protective action of caeruloplasmin.

Normal human plasma does not contain low molecular mass iron because the iron-binding protein transferrin retains a considerable iron-binding capacity. In conditions of iron-overload, however, low molecular mass iron can be detected in plasma. Plasma contains several molecules capable of reducing ferric complexes to the ferrous state and this could lead to oxidative damage through reactions dependent on Fenton chemistry and lipid peroxidation. It seems likely that ascorbate and urate would reduce ferric complexes present in plasma during iron-overload. However, the plasma, 'ferroxidase' protein caeruloplasmin protects the extracellular environment by catalytically oxidising ferrous complexes back to the less reactive ferric state.

2,2'-Dipyridyl↗
PubMed1991

Hemochromatosis, iron and septicemia caused by Vibrio vulnificus.

Vibrio vulnificus is killed by normal human blood but grows rapidly in blood from patients with hemochromatosis. It also grows in normal blood if the saturation of the transferrin is increased or if hematin, which contains iron, is added. It is suggested that the increased availability of iron in the blood of patients with chronic iron overload is responsible for their enhanced susceptibility to infection with V vulnificus.

Female↗
PubMed1990

Superoxide dismutase and Fenton chemistry. Reaction of ferric-EDTA complex and ferric-bipyridyl complex with hydrogen peroxide without the apparent formation of iron(II).

A ferric-EDTA complex, prepared directly from FeCl3 or from an oxidized ferrous salt, reacts with H2O2 to form hydroxyl radicals (.OH), which degrade deoxyribose and benzoate with the release of thiobarbituric acid-reactive material, hydroxylate benzoate to form fluorescent dihydroxy products and react with 5,5-dimethylpyrrolidine N-oxide (DMPO) to form a DMPO-OH adduct. Degradation of deoxyribose and benzoate and the hydroxylation of benzoate are substantially inhibited by superoxide dismutase and .OH-radical scavengers such as formate, thiourea and mannitol. Inhibition by the enzyme superoxide dismutase implies that the reduction of the ferric-EDTA complex for participation in the Fenton reaction is superoxide-(O2.-)-dependent, and not H2O2-dependent as frequently implied. When ferric-bipyridyl complex at a molar ratio of 1:4 is substituted for ferric-EDTA complex (molar ratio 1:1) and the same experiments are conducted, oxidant damage is low and deoxyribose and benzoate degradation were poorly if at all inhibited by superoxide dismutase and .OH-radical scavengers. Benzoate hydroxylation, although weak, was, however, more effectively inhibited by superoxide dismutase and .OH-radical scavengers, implicating some role for .OH. The iron-bipyridyl complex had available iron-binding capacity and therefore would not allow iron to remain bound to buffer or detector molecules. Most .OH radicals produced by the iron-bipyridyl complex and H2O2 are likely to damage the bipyridyl molecules first, with few reacting in free solution with the detector molecules. Deoxyribose and benzoate degradation appeared to be mediated by an oxidant species not typical of .OH, and species such as the ferryl ion-bipyridyl complex may have contributed to the damage observed.

2,2'-Dipyridyl↗
PubMed1990

Methylene blue plus light mediates 8-hydroxy 2'-deoxyguanosine formation in DNA preferentially over strand breakage.

Methylene blue (MB) plus light, in the presence of oxygen, mediates formation of 8-hydroxyguanine in DNA. The yield of 8-hydroxyguanine may be as much as from 2 to 4% of the guanines present. The results presented here show that treatment of supercoiled plasmid DNA with methylene blue plus light causes single-stranded nicks. However, single-stranded nicking occurs approximately 17-fold less frequently than does formation of 8-hydroxyguanine. The nicking rate is reduced in the presence of Mg ion but is not prevented by inhibitors of the iron-catalyzed Fenton reaction or by scavengers of hydroxyl free radicals. Extensive exposure of DNA to light in the presence of MB produces no detectable thiobarbital reactive material thus implicating that single strand nicking does not occur by hydroxyl free radical attack on deoxyribose. Formation of 8-hydroxyguanine is apparently not dependent upon intercalative binding of MB to DNA, since it is formed in polydeoxyguanylic acid.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1990

The antioxidants of human extracellular fluids.

The antioxidants in the aqueous phase of human plasma include ceruloplasmin, albumin (the protein itself and possibly also albumin-bound bilirubin), ascorbic acid, transferrin, haptoglobin, and hemopexin. Assays that attempt to answer the question "what is the most important antioxidant?" are compared, it being concluded that the answer is different depending on the nature of the prooxidant stress imposed in the assay.

Antioxidants↗
PubMed1990

ADP-iron as a Fenton reactant: radical reactions detected by spin trapping, hydrogen abstraction, and aromatic hydroxylation.

A mixture of ADP, ferrous ions, and hydrogen peroxide (H2O2) generates hydroxyl radicals (OH) that attack the spin trap DMPO (5,5-dimethyl-pyrollidine-N-oxide) to yield the hydroxyl free radical spin-adduct, degrade deoxyribose and benzoate with the release of thiobarbituric acid-reactive material, and hydroxylate benzoate to give fluorescent products. Inhibition studies, with scavengers of the OH radical, suggest that the behavior of iron-ADP in the reaction is complicated by the formation of ternary complexes with certain scavengers and detector molecules. In addition, iron-ADP reacting with H2O2 appears to release a substantial number of OH radicals free into solution. During the generation of OH radicals the ADP molecule was, as expected, damaged by the iron bound to it. Damage to the iron ligand in this way is not normally monitored in reaction systems that use specific detector molecules for OH radical damage. Under certain reaction conditions the ligand may be the major recipient of OH radical damage thereby leading to the incorrect assumption that the iron ligand is a poor Fenton reactant.

Adenosine Diphosphate↗
PubMed1990

The measurement and mechanism of lipid peroxidation in biological systems.

The basic chemistry of the propagation of lipid peroxidation reactions has been known for years, but the mechanism of initiation of this process in biological membrane systems is still uncertain. Currently available assays for measuring peroxidation are reviewed--the more specific the assay used, the less peroxide is found in healthy human tissues and body fluids. Lipid peroxidation can arise as a consequence of tissue injury in many disease states and may sometimes contribute significantly to worsening the tissue injury.

Free Radicals↗
PubMed1990

Superoxide-dependent formation of hydroxyl radicals from ferric-complexes and hydrogen peroxide: an evaluation of fourteen iron chelators.

When a variety of ferric chelates are reacted with hydrogen peroxide in phosphate buffer deoxyribose is damaged and this damage is protected against by formate, thiourea and mannitol. Damage done by ferric complexes of citrate, EDTA, NTA, EGTA and HEDA is substantially inhibited by superoxide dismutase (SOD) whereas complexes of PLA, ADP and CDTA are moderately inhibited by SOD. The effects of SOD argue against hydrogen peroxide acting as a reductant in Fenton chemistry driven by ferric complexes and hydrogen peroxide. EDTA has proved to be a useful model for Fenton chemistry that is inhibited by SOD although, it is not unique in this respect.

Chemical Phenomena↗
PubMed1990

Bleomycin-iron damage to DNA with formation of 8-hydroxydeoxyguanosine and base propenals. Indications that xanthine oxidase generates superoxide from DNA degradation products.

Bleomycin, in the presence of ferric salts, oxygen and a suitable reductant, degrades DNA with the release of base propenals, detected as thiobarbituric acid (TBA) reactivity, and the formation of 8-hydroxydeoxyguanosine (8OHdG) detected by HPLC. When xanthine oxidase is added to the incubated mixture of DNA degradation products, TBA-reactivity is destroyed but 8OHdG formation is increased. EPR Spin trapping experiments show that hydroxyl radicals (OH) are formed in the reaction mixture and can be inhibited by the inclusion of either superoxide dismutase or catalase. These findings suggest that the base propenals and possibly malondialdehyde, formed from them, are aldehydic substrates for xanthine oxidase and, the product of this reaction is superoxide (O2-) and hydrogen peroxide (H2O2). Thus, TBA reactivity is destroyed in the formation of O2- and H2O2 which stimulate further oxidative damage to DNA resulting in increased 8OHdG formation.

8-Hydroxy-2'-Deoxyguanosine↗
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

Iron and oxygen: a biologically damaging mixture.

Iron is a remarkably useful metal in Nature, but iron ions not safely sequestered in storage or transport proteins are hazardous because they can stimulate damaging free radical reactions. Biological examples of these are Fenton Chemistry leading to the formation of highly reactive species, such as the hydroxyl radical (.OH) and the ferryl ion (FeO2+), and lipid peroxidation. The need to conserve body iron stores has closely evolved with an essential requirement for antioxidant protection and, several 'acute-phase' proteins involved in iron metabolism such as caeruloplasmin, haptoglobins and haemopexin in collaboration with the iron binding proteins transferrin and lactoferrin contribute to our defense against oxidative damage.

Antioxidants↗
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

Antioxidant protection by haemopexin of haem-stimulated lipid peroxidation.

Haem (ferrous protoporphyrin IX) is a reactive low-molecular-mass form of iron able to participate in oxygen-radical reactions that can lead to the degradation of proteins, lipids, carbohydrates and DNA. Oxygen-radical reactions are likely to occur upon tissue damage. Extracellular fluids rely on antioxidant mechanisms different from those found inside the cell, and circulating proteins limit radical reactions by converting pro-oxidant forms of iron into less-reactive forms. Of the compounds tested, only apohaemopexin and the chain-breaking antioxidant butylated hydroxytoluene inhibited (by more than 90%) haemin-stimulated peroxidation as measured by formation of conjugated dienes, thiobarbituric acid-reactive material from linolenic acid or peroxidation-induced phospholipid fluorescence. Haptoglobin, the haemoglobin-binding serum protein, was ineffective. Conversely, only haptoglobin significantly inhibited haemoglobin-stimulated lipid peroxidation. Iron-salt-induced lipid peroxidation was inhibited only by apotransferrin and the iron-chelator desferrioxamine. All lipid peroxidations were inhibited by the radical scavengers butylated hydroxytoluene and propyl gallate. These findings support the concept that transport and conservation of body iron stores are closely linked to antioxidant protection.

Antioxidants↗
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↗