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Biomedical subjects

B Halliwell

Publications and source records attributed to B Halliwell.

At least 325 records · Page 18Linked to original sources
PubMed1988

Oxidants, inflammation, and anti-inflammatory drugs.

Species such as superoxide radical (O2-), hydrogen peroxide (H2O2), hydroxyl radical (.OH), and hypochlorous acid (HOCl) can be formed in vivo, e.g., by activated phagocytic cells. Generation of .OH from H2O2 in vivo usually involves iron-dependent reactions. Good evidence exists for increased generation of oxidants in vivo in patients with active rheumatoid disease, but the contribution of these oxidants to the disease process is still uncertain. The likelihood that anti-inflammatory drugs used in the treatment of arthritis could act by scavenging oxidants or preventing their formation is discussed.

Anti-Inflammatory Agents↗
PubMed1988

The iron-binding and hydroxyl radical scavenging action of anti-inflammatory drugs.

1. Hydroxyl radicals (.OH) are thought to be generated at sites of inflammation and to contribute to tissue damage. All anti-inflammatory drugs tested were able to scavenge .OH generated in free solution at almost diffusion-controlled rates (rate constants about 10(10)M-1s-1). 2. Much .OH generation in vivo occurs at specific sites, where bound metal ions (such as Fe2+) react with H2O2 to produce .OH that immediately attacks the site. Only .OH scavengers that have sufficient metal-binding ability to withdraw metal ions from this site can protect against site-specific damage. 3. All anti-inflammatory drugs tested were able to protect against site-specific damage by .OH in a simple model system in vitro. Penicillamine, diclofenac sodium, piroxicam, azathioprine, primaquine, chloroquine and hydroxychloroquine were especially effective. 4. The ability of an anti-inflammatory drug to protect against .OH formation in vivo depends not only on its rate constant for reaction with .OH, but also on its metal-binding ability and on the geometry and redox potential of any metal complex formed.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1988

On the specificity of allopurinol and oxypurinol as inhibitors of xanthine oxidase. A pulse radiolysis determination of rate constants for reaction of allopurinol and oxypurinol with hydroxyl radicals.

Allopurinol has been employed as a "specific" inhibitor of xanthine oxidase in studies of hypoxic/reoxygenation injury. Pulse radiolysis was used to establish rate constants for the reactions of allopurinol and its major metabolite oxypurinol with hydroxyl radicals: values were (1.45 +/- 0.24) x 10(9) M-1 s-1 for allopurinol and (4.95 +/- 0.84) x 10(9) M-1 s-1 for oxypurinol. These rate constants show that, in view of the amounts of allopurinol that have been used in animal studies, hydroxyl radical scavenging by this molecule could contribute to its biological actions, especially if animals are pre-treated with allopurinol, so allowing oxypurinol to form. The ability of allopurinol to protect tissues not containing xanthine oxidase against reoxygenation injury may be related to radical scavenging by allopurinol and oxypurinol.

Allopurinol↗
PubMed1988

Formation of hydroxyl radicals in biological systems. Does myoglobin stimulate hydroxyl radical formation from hydrogen peroxide?

Incubation of horse-heart oxymyoglobin or metmyoglobin with excess H2O2 causes formation of myoglobin(IV), followed by haem degradation. At the time when haem degradation is observed, hydroxyl radicals (.OH) can be detected in the reaction mixture by their ability to degrade the sugar deoxyribose. Detection of hydroxyl radicals can be decreased by transferrin or by .OH scavengers (mannitol, arginine, phenylalanine) but not by urea. Neither transferrin nor any of these scavengers inhibit the haem degradation. It is concluded that intact oxymyoglobin or metmyoglobin molecules do not react with H2O2 to form .OH detectable by deoxyribose, but that H2O2 eventually leads to release of iron ions from the proteins. These released iron ions can react to form .OH outside the protein or close to its surface. Salicylate and the iron chelator desferrioxamine stabilize myoglobin and prevent haem degradation. The biological importance of .OH generated using iron ions released from myoglobin by H2O2 is discussed in relation to myocardial reoxygenation injury.

Animals↗
PubMed1988

Nontransferrin-bound iron in plasma from hemochromatosis patients: effect of phlebotomy therapy.

Plasma from patients with iron overload resulting from idiopathic hemochromatosis contains nontransferrin-bound iron, measurable by the bleomycin, assay. During venesection therapy, the concentration of bleomycin iron declines in a way highly correlated with plasma ferritin concentrations. Even when patients had been venesected to give very low total plasma iron concentrations and high transferrin iron-binding capacity, bleomycin-detectable iron was still present at low concentrations. Bleomycin-detectable iron can stimulate damaging free radical reactions, and its persistence in plasma even after prolonged venesection might contribute to the tissue damage that results from iron overload.

Adult↗
PubMed1987

Action of hypochlorous acid on the antioxidant protective enzymes superoxide dismutase, catalase and glutathione peroxidase.

The neutrophil enzyme myeloperoxidase generates hypochlorous acid (HOCl) at sites of inflammation. Glutathione peroxidase is very quickly inactivated by low concentration of HOCl. Inactivation of catalase is also rapid, but requires higher HOCl concentrations and the haem appears to be degraded. Inactivation of bovine CuZn superoxide dismutase is slower. Hence superoxide dismutase should not be easily inactivated by HOCl at sites of inflammation, which may contribute to its effectiveness as an anti-inflammatory agent and in minimizing reperfusion injury.

Blood Proteins↗
PubMed1987

Biologically-significant scavenging of the myeloperoxidase-derived oxidant hypochlorous acid by some anti-inflammatory drugs.

Neutrophils contain the enzyme myeloperoxidase, which oxidizes Cl- ions into the powerful oxidant hypochlorous acid (HOCl). HOCl inactivates alpha 1-antiprotease, permitting uncontrolled protease activities. Most anti-inflammatory drugs tested are capable of reacting with HOCl, but the reactions seem insufficiently rapid under physiological conditions to protect alpha 1-antiprotease against inactivation by HOCl. However, rapid scavenging of HOCl might contribute to the anti-inflammatory effects of penicillamine, gold sodium thiomalate, phenylbutazone and primaquine.

Animals↗
PubMed1987

The scavenging of oxidants by sulphasalazine and its metabolites. A possible contribution to their anti-inflammatory effects?

Sulphasalazine (Salazopyrin) and its metabolites sulphapyridine and 5-aminosalicylate are powerful scavengers of the hydroxyl radical, determined by pulse radiolysis and confirmed by assays based on deoxyribose degradation by hydroxyl radicals. 5-Aminosalicylate can also protect alpha 1-antiprotease against attack by the myeloperoxidase-derived oxidant hypochlorous acid. The ability to scavenge oxidants produced at sites of inflammation may contribute to the anti-inflammatory action of sulphasalazine and its metabolites.

Aminosalicylic Acids↗
PubMed1987

The deoxyribose method: a simple "test-tube" assay for determination of rate constants for reactions of hydroxyl radicals.

Hydroxyl radicals, generated by reaction of an iron-EDTA complex with H2O2 in the presence of ascorbic acid, attack deoxyribose to form products that, upon heating with thiobarbituric acid at low pH, yield a pink chromogen. Added hydroxyl radical "scavengers" compete with deoxyribose for the hydroxyl radicals produced and diminish chromogen formation. A rate constant for reaction of the scavenger with hydroxyl radical can be deduced from the inhibition of color formation. For a wide range of compounds, rate constants obtained in this way are similar to those determined by pulse radiolysis. It is suggested that the deoxyribose assay is a simple and cheap alternative to pulse radiolysis for determination of rate constants for reaction of most biological molecules with hydroxyl radicals. Rate constants for reactions of ATP, ADP, and Good's buffers with hydroxyl radicals have been determined by this method.

Ascorbic Acid↗
PubMed1987

Measurement of allantoin and uric acid in human body fluids. A potential index of free-radical reactions in vivo?

Free-radical attack upon uric acid generates allantoin [Ames, Cathcart, Schwiers & Hochstein (1981) Proc. Natl. Acad. Sci. U.S.A. 78, 6858-6862]. Methods are described for the accurate measurement of uric acid and allantoin in human body fluids. The concentrations of uric acid and allantoin in human serum and synovial fluid are reported. It is suggested that measurement of changes in allantoin concentration may be a useful index of free-radical reactions taking place in vivo.

Allantoin↗
PubMed1987

The specificity of thiourea, dimethylthiourea and dimethyl sulphoxide as scavengers of hydroxyl radicals. Their protection of alpha 1-antiproteinase against inactivation by hypochlorous acid.

Thiourea and dimethylthiourea are powerful scavengers of hydroxyl radicals (.OH), and dimethylthiourea has been used to test the involvement of .OH in several animal models of human disease. It is shown that both thiourea and dimethylthiourea are scavengers of HOCl, a powerful oxidant produced by neutrophil myeloperoxidase. Hence the ability of dimethylthiourea to protect against neutrophil-mediated tissue damage cannot be used as evidence for a role of .OH in causing such damage. Dimethyl sulphoxide also reacts with HOCl, but at a rate that is probably too low to be biologically significant at dimethyl sulphoxide concentrations up to 10 mM. Neither mannitol nor desferrioxamine, at the concentrations normally used in radical-generating systems, appears to react with HOCl.

Deferoxamine↗
PubMed1987

The antioxidant action of human extracellular fluids. Effect of human serum and its protein components on the inactivation of alpha 1-antiproteinase by hypochlorous acid and by hydrogen peroxide.

The elastase-inhibitory capacity of purified human alpha 1-antiproteinase is inactivated by low concentrations of the myeloperoxidase-derived oxidant hypochlorous acid, but much higher concentrations are required to inhibit the elastase-inhibitory capacity of serum samples. The protective effect of serum appears to be largely due to albumin. High concentrations of H2O2 also inactivate the elastase-inhibitory capacity of alpha 1-antiproteinase, by a mechanism not involving formation of hydroxyl radicals. Serum offers protection against H2O2 inactivation of alpha 1-antiproteinase. The relevance of these results to the tissue damage produced by activated phagocytes is discussed.

Blood↗
PubMed1987

Biologically significant scavenging of the myeloperoxidase-derived oxidant hypochlorous acid by ascorbic acid. Implications for antioxidant protection in the inflamed rheumatoid joint.

Ascorbic acid, at physiological concentrations, can scavenge the myeloperoxidase-derived oxidant hypochlorous acid at rates sufficient to protect alpha 1-antiprotease against inactivation by this molecule. The rapid depletion of ascorbic acid at sites of inflammation, as in the inflamed rheumatoid joint, may therefore facilitate proteolytic damage.

Antioxidants↗