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Biomedical subjects

B Halliwell

Publications and source records attributed to B Halliwell.

At least 307 records · Page 17Linked to original sources
PubMed1989

Marked reduction of free radical generation and contractile dysfunction by antioxidant therapy begun at the time of reperfusion. Evidence that myocardial "stunning" is a manifestation of reperfusion injury.

Recent evidence suggests that postischemic myocardial dysfunction ("stunning") may be mediated by oxygen free radicals, but the exact time window during which the critical radical-mediated damage develops remains unknown. Furthermore, the evidence for the oxyradical hypothesis is indirect and, therefore, inconclusive. Thus, the potent and cell-permeable antioxidant N-(2-mercaptopropionyl)-glycine (MPG) was administered as an intra-coronary infusion (8 mg/kg/hr) to three groups of open-chest dogs undergoing a 15-minute coronary occlusion followed by 4 hours of reperfusion. In group I (n = 8), the infusion of MPG was started 15 minutes before occlusion and ended 2 hours after reperfusion; in group II (n = 9), MPG was started 1 minute before reperfusion and ended 2 hours thereafter; in group III (n = 10), MPG was started 1 minute after reperfusion and ended 2 hours and 15 minutes thereafter. Control dogs (group IV) (n = 10) received vehicle. Recovery of contractile function (assessed as systolic wall thickening) was equivalent in groups I and II, and in both groups it was substantially greater than in controls (p less than 0.005 at 4 hours). In contrast, in group III recovery of function was indistinguishable from controls. To determine whether the protection afforded by MPG was due to inhibition of free radical reactions, myocardial production of free radicals was directly assessed by intracoronary infusion of the spin trap alpha-phenyl N-tert-butyl nitrone (PBN). In control dogs (group VII, n = 6), radical adducts of PBN were released in the coronary venous blood after reperfusion, with a burst occurring in the first 5 minutes. MPG given as in group II (group V, n = 5) markedly suppressed myocardial production of PBN adducts (delta = -98% over 3 hours, p less than 0.01 vs. controls); this effect was evident immediately after reperfusion. MPG given as in group III (group VI, n = 5) also suppressed PBN adduct production (delta = -83% over 3 hours, p less than 0.025 vs. controls), but this effect was delayed. Hence, the radicals important in myocardial stunning appear to be those generated immediately after reperfusion. In vitro studies demonstrated that MPG is an exceptionally powerful scavenger of .OH (rate constant = 8.1 x 10(9) M-1 sec-1 by pulse radiolysis) but has no significant effect on .O2- (rate constant less than 10(3) M-1 sec-1), H2O2 (rate constant = 1.6 M-1 sec-1), or non-.OH-initiated lipid peroxidation, suggesting that removal of .OH is the major mechanism of the beneficial effects of MPG.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Superoxide, iron, vascular endothelium and reperfusion injury.

It is proposed that vascular endothelium has an intrinsic capacity to generate O2- for regulatory purposes such as inactivation of endothelium-derived relaxing factor. Ischaemia can disrupt the functioning of this oxidant-generating system, resulting in greater O2- generation when O2 is restored. Ischaemia-induced cellular injury can also lead to release of iron ions, that, upon reperfusion, cause conversion of O2- and H2O2 to powerfully-oxidizing species (such as .OH) that further injure the endothelium.

Animals↗
PubMed1989

Oxidation of dimethylsulphoxide to formaldehyde by oxyhaemoglobin and oxyleghaemoglobin in the presence of hydrogen peroxide is not mediated by "free" hydroxyl radicals.

In the presence of excess hydrogen peroxide, human oxyhaemoglobin and oxyleghaemoglobin from soybean root nodules cause oxidation of dimethylsulphoxide to formaldehyde. This reaction is inhibited by thiourea but not by phenylalanine, HEPES, mannitol or arginine. It is concluded that dimethylsulphoxide oxidation is not mediated by "free" hydroxyl radicals, consistent with previous conclusions that intact haemoglobin, leghaemoglobin or myoglobin molecules do not react with H2O2 to form hydroxyl radicals detectable outside the protein.

Dimethyl Sulfoxide↗
PubMed1989

Non-caeruloplasmin copper and ferroxidase activity in mammalian serum. Ferroxidase activity and phenanthroline-detectable copper in human serum in Wilson's disease.

It is thought that 5-10% of human serum copper consists of copper ions complexed with histidine, amino acids or albumin. The phenanthroline assay developed by Gutteridge (Biochem. J. 218, 983-985; 1984) is shown to measure all these forms of copper down to a sensitivity of 0.1 mumol/dm3, yet it does not detect any copper ions in freshly-prepared serum or plasma from rats, mice, rabbits or guinea-pigs, or freshly-prepared serum from humans. It is concluded that the "non-caeruloplasmin copper pool" is much smaller than has previously been supposed. No phenanthroline-detectable copper could be measured in serum freshly prepared from four patients with uncomplicated Wilson's disease, but it could be measured in serum from a patient with fulminant hepatic failure. After liver transplantation, concentrations of phenanthroline-detectable copper in this patient fell to zero within two days. Studies on the ferroxidase activity of freshly-prepared serum or plasma samples shows that little ferroxidase II activity is present in samples from healthy adults or from the patient with Wilson's disease and fulminant hepatic failure. In all the patients, ferroxidase I activities are sub-normal. Freshly-prepared plasma or serum samples from several animal species generally show lower ferroxidase I and greater ferroxidase II activities than do human samples, but only in rabbits does ferroxidase II account for a high proportion of total plasma ferroxidase activity. Storage of biological fluids can cause release of copper from caeruloplasmin and a rise in ferroxidase II activity; these events may have confused some earlier studies.

Adult↗
PubMed1988

Bleomycin-detectable iron in serum from leukaemic patients before and after chemotherapy. Therapeutic implications for treatment with oxidant-generating drugs.

Patients with acute myeloid leukaemia show elevated plasma iron and, in 2/6 cases studied, low-molecular-mass iron complexes capable of stimulating radical reactions were present in the plasma. Shortly after the onset of chemotherapy, there is a sharp rise in transferrin saturation and all patients studied showed low-molecular-mass iron in their plasma. It is proposed that such iron could interact with oxidants generated by certain drugs (e.g. adriamycin or daunorubicin) to facilitate tissue damage, and that some of the side-effects of chemotherapy might be ameliorated by careful co-administration of small doses of desferrioxamine.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

The antioxidant action of taurine, hypotaurine and their metabolic precursors.

It has been suggested that taurine, hypotaurine and their metabolic precursors (cysteic acid, cysteamine and cysteinesulphinic acid) might act as antioxidants in vivo. The rates of their reactions with the biologically important oxidants hydroxyl radical (.OH), superoxide radical (O2.-), hydrogen peroxide (H2O2) and hypochlorous acid (HOCl) were studied. Their ability to inhibit iron-ion-dependent formation of .OH from H2O2 by chelating iron ions was also tested. Taurine does not react rapidly with O2.-, H2O2 or .OH, and the product of its reaction with HOCl is still sufficiently oxidizing to inactivate alpha 1-antiproteinase. Thus it seems unlikely that taurine functions as an antioxidant in vivo. Cysteic acid is also poorly reactive to the above oxidizing species. By contrast, hypotaurine is an excellent scavenger of .OH and HOCl and can interfere with iron-ion-dependent formation of .OH, although no reaction with O2.- or H2O2 could be detected within the limits of our assay techniques. Cysteamine is an excellent scavenger of .OH and HOCl; it also reacts with H2O2, but no reaction with O2.- could be measured within the limits of our assay techniques. It is concluded that cysteamine and hypotaurine are far more likely to act as antioxidants in vivo than is taurine, provided that they are present in sufficient concentration at sites of oxidant generation.

Antioxidants↗
PubMed1988

Iron, copper and zinc concentrations in human sweat and plasma; the effect of exercise.

The effect of 30 or 40 min hard exercise on a cycle ergometer upon plasma concentrations of zinc, iron and copper in twelve healthy male athletes was studied. Sweat samples were also collected from different body sites and analyzed for these metals. The metal content of sweat from different body sites varied, as did the sweating rates of different subjects. Pre-exercise plasma iron concentrations in 10 of the 12 subjects were within the normal range, but at least 4 subjects had sub-normal plasma zinc whereas six had plasma copper levels above normal. The effects of exercise on plasma metal concentrations varied from subject to subject; no general conclusions could be drawn about the biological significance of loss of metals in sweat in relation to whole body metal metabolism. It is suggested that a mild acute phase response may account for lowered zinc and raised copper in the plasma of athletes.

Adult↗
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

Aromatic hydroxylation of phenylalanine as an assay for hydroxyl radicals: application to activated human neutrophils and to the heme protein leghemoglobin.

Attack of hydroxyl radical (.OH), generated by a Fenton system at physiological pH, upon L-phenylalanine produces three isomeric tyrosines, o-tyrosine (2-hydroxyphenylalanine), m-tyrosine (3-hydroxyphenylalanine), and p-tyrosine (4-hydroxyphenylalanine). These may be separated by high-performance liquid chromatography and measured using an electrochemical detector. Since L-phenylalanine is relatively nontoxic, it is proposed that generation of these three tyrosines from phenylalanine can be used as an assay for .OH in biological systems. The use of the assay to measure .OH production by leghemoglobin (plus H2O2) and by activated human neutrophils is described. No .OH production by activated human neutrophils was observed unless a source of iron ions was added to the reaction mixture, which suggests that these cells do not release an iron "promoter" of .OH generation from superoxide and hydrogen peroxide.

Chromatography, High Pressure Liquid↗
PubMed1988

2,3-Dihydroxybenzoic acid is a product of human aspirin metabolism.

2,3-Dihydroxybenzoic acid is present in blood plasma and urine of healthy human volunteers after aspirin ingestion. Its identity has been confirmed by mass spectrometry and by electrochemical analysis. Methods for its identification and measurement are described. The concentration of 2,3-dihydroxybenzoic acid is much lower than that of 2,5-dihydroxybenzoic acid, salicylic acid or salicyluric acid.

Aspirin↗
PubMed1988

Formation of hydroxyl radicals from hydrogen peroxide in the presence of iron. Is haemoglobin a biological Fenton reagent?

The ability of oxyhaemoglobin and methaemoglobin to generate hydroxyl radicals (OH.) from H2O2 has been investigated using deoxyribose and phenylalanine as 'detector molecules' for OH.. An excess of H2O2 degrades methaemoglobin, releasing iron ions that react with H2O2 to form a species that appears to be OH.. Oxyhaemoglobin reacts with low concentrations of H2O2 to form a 'reactive species' that degrades deoxyribose but does not hydroxylate phenylalanine. This 'reactive species' is less amenable to scavenging by certain scavengers (salicylate, phenylalanine, arginine) than is OH., but it appears more reactive than OH. is to others (Hepes, urea). The ability of haemoglobin to generate not only this 'reactive species', but also OH. in the presence of H2O2 may account for the damaging effects of free haemoglobin in the brain, the eye, and at sites of inflammation.

Deoxyribose↗