Search PubMed⌕ Search

Biomedical subjects

B Halliwell

Publications and source records attributed to B Halliwell.

At least 181 records · Page 10Linked to original sources
PubMed1995

Effect of the hydrophilic alpha-tocopherol analog MDL 74,405 on detection of hydroxyl radicals in stunned myocardium in dogs.

We have previously shown in dogs that the hydrophilic alpha-tocopherol analog, MDL 74,405, attenuates postischemic myocardial dysfunction ("stunning") and generation of free radicals as assessed with the spin trap alpha-phenyl N-tert-butyl nitrone (PBN). However, we could not discern whether this drug acts on primary radicals (such as hydroxyl radical [.OH]) or on secondary radicals. The goal of this study was to directly determine whether the beneficial effects of MDL 74,405 result from actions against .OH. Open-chest dogs undergoing a 15-minute coronary artery occlusion and 3 hours of reperfusion received an intravenous infusion of either saline solution (control group, n = 7) or MDL 74,405 (n = 6) starting 30 minutes before coronary occlusion and ending 60 minutes after reflow at a dose of 0.3 mg/kg/hr. Formation of .OH was estimated by the technique of aromatic hydroxylation of phenylalanine. Phenylalanine was infused intravenously, and the plasma concentrations of the hydroxylated products ortho-, meta-, and para-tyrosines (o-, m-, and p-tyr) in the coronary venous effluent and in the arterial blood were measured with high-performance liquid chromatography. In the control group a dramatic increase in the myocardial release of o-, m-, and p-tyr was observed immediately after reperfusion; the release of tyrosines peaked at 1 minute of reflow and continued up to 10 minutes after reperfusion. MDL 74,405 abolished the release of o-tyr throughout the first 10 minutes of reperfusion but had a less pronounced effect on the production of m- and p-tyr. These results demonstrate that MDL 74,405 is effective in inhibiting .OH-initiated reactions in the postischemic stunned myocardium in the dog, suggesting that the anti-.OH action of MDL 74,405 is an important mechanism of action of this antioxidant.

Animals↗
PubMed1995

The characterization of antioxidants.

The role of antioxidants in nutrition is an area of increasing interest. Antioxidants are used (1) to prolong the shelf life and maintain the nutritional quality of lipid-containing foods, and (2) to modulate the consequences of oxidative damage in the human body. This review discusses what an antioxidant is and how the properties of antioxidants may be characterized.

Antioxidants↗
PubMed1995

How to characterize an antioxidant: an update.

The term antioxidant is widely used but rarely defined. One suggested definition is that an antioxidant is 'a substance that, when present at low concentrations compared with those of an oxidizable substrate, significantly delays or prevents oxidation of that substrate'. Many substances have been suggested to act as antioxidants in vivo, but few have been proved to do so. This chapter addresses the criteria necessary to evaluate a proposed antioxidant activity. Simple methods for assessing the possibility of physiologically feasible scavenging of important biological oxygen-derived species (superoxide, hydrogen peroxide, hydroxyl radical, hypochlorous acid, haem-associated ferryl species, radicals derived from activated phagocytes and peroxyl radicals, both lipid-soluble and water-soluble) are presented. Methods that may be used to gain evidence that a compound actually does function as an antioxidant in vivo are discussed.

Antioxidants↗
PubMed1995

Oxidative damage by ozone and nitrogen dioxide: synergistic toxicity in vivo but no evidence of synergistic oxidative damage in an extracellular fluid.

Inhalation of ozone (O3) and/or nitrogen dioxide (.NO2) is associated with the development of inflammation in the respiratory tract and various alterations in pulmonary functions. Respiratory tract lining fluids (RTLFs) represent the first biological fluids coming into contact with these inhaled toxicants. Using plasma as a surrogate for RTLFs, we have previously shown that O3 [Cross, Motchnik, Bruener, Jones, Kaur, Ames and Halliwell (1992) FEBS Lett. 298, 269-272] and .NO2 [Halliwell, Hu, Louie, Duvall, Tarkington, Motchnik and Cross (1992) FEBS Lett. 313, 62-66] are both capable of depleting antioxidants and damaging proteins and lipids. O3 particularly damages proteins, whereas .NO2 induces the peroxidation of lipids and nitrates aromatic amino acids. It has been reported that O3 and .NO2 cause synergistic toxicity in rodents [Gielzleichter, Witschi and Last (1992) Tox. Appl. Pharmacol. 116, 1-9]. In the present chapter, we review evidence showing that combined exposure of these two oxidant gases to human plasma fails to exert synergistic oxidative damage to plasma constituents, and in fact, O3 and .NO2 antagonize each other's actions. We conclude that the potentiating effect of these two gases on morbidity and mortality in rodents represents a complex interactive biological effect rather than a simple synergistic oxidative effect in extracellular fluids.

Animals↗
PubMed1995

Side-effects of drugs used in the treatment of rheumatoid arthritis.

A number of anti-inflammatory and other drugs used in the treatment of rheumatoid arthritis have been screened for their ability to cause oxidative damage to lipids and proteins in vitro. Although many drugs exhibited an antioxidant profile, a few drugs tested were pro-oxidant, increasing peroxidation of arachidonic acid by mixtures of haem proteins and H2O2. This system may be an appropriate model to use in the inflammatory situation, since microbleeding to release haemoglobin occurs in the inflamed rheumatoid joint, where H2O2 is produced by invading neutrophils. The damaging effects of the pro-oxidant drugs phenylbutazone, meclofenamic acid and flufenamic acid were investigated in some detail using this system. Arachidonic acid peroxidation was accentuated in a dose-dependent manner and in the presence of haem proteins and H2O2, phenylbutazone also causes inactivation of alpha 1-antiproteinase, a major serine proteinase inhibitor in biological fluids. The above drugs may interact with ferryl haemoglobin, produced by the reaction of H2O2 with haemoglobin, to generate drug-derived radicals causing oxidative damage in these systems. If such reactions occur in vivo, they could contribute to the side-effects induced by these drugs on administration to certain rheumatoid arthritis patients.

Adrenal Cortex Hormones↗
PubMed1995

Free radicals and antioxidants in food and in vivo: what they do and how they work.

A wide variety of oxygen free radicals and other reactive oxygen species can be formed in the human body and in food systems. Transition metal ions accelerate free-radical damage. Antioxidant defenses, both enzymic and nonenzymic, protect the body against oxidative damage, but they are not 100% efficient, and so free-radical damage must be constantly repaired. Nonenzymatic antioxidants are frequently added to foods to prevent lipid peroxidation. Several lipid antioxidants can exert prooxidant effects toward other molecules under certain circumstances, and so antioxidants for food and therapeutic use must be characterized carefully. Methods of measuring oxidative damage and trapping free radicals in vivo are briefly discussed. Such methods are essential in checking proposals that increased intake of food-derived antioxidants (such as antioxidant vitamins) would be beneficial to humans.

Antioxidants↗
PubMed1995

Oxidation of low-density lipoproteins: questions of initiation, propagation, and the effect of antioxidants.

Oxidation of low-density lipoproteins (LDLs) plays a role in the development of atherosclerosis, but many questions remain unanswered. This paper aims to evaluate critically the available data pertinent to the following questions: 1) How is LDL oxidation initiated, especially in early atherosclerotic lesions? 2) Is nitric oxide good or bad in lesions? and 3) Which antioxidants are really important in protecting LDLs against oxidation in the human body?

Antioxidants↗
PubMed1995

Dietary antioxidants and cigarette smoke-induced biomolecular damage: a complex interaction.

Epidemiologic evidence suggests that cigarette smoking is a major risk factor for chronic obstructive pulmonary diseases such as chronic bronchitis and emphysema, for carcinogenesis, and for cardiovascular disease. However, the precise mechanisms of these effects are incompletely understood. The gas phase of cigarette smoke contains abundant free radicals including nitric oxide. Hence, cigarette smoke may induce some of its damaging effects by free radical mechanisms. We report that exposure of plasma, a model for respiratory tract lining fluids, to gas-phase cigarette smoke causes depletion of antioxidants, including ascorbate, urate, ubiquinol-10, and alpha-tocopherol, and a variety of carotenoids, including beta-carotene. Gas-phase cigarette smoke induced some lipid peroxidation, as measured by cholesteryl linoleate hydroperoxide (18:2OOH) formation. Ascorbate was effective in preventing 18:2OOH formation. In contrast to the low concentrations of lipid hydroperoxides measured (< 1 mumol/L), protein carbonyl formation, a measure of protein modification, increased by approximately 400 mumol/L after nine puffs of cigarette smoke. Reduced glutathione inhibited protein carbonyl formation, whereas other plasma antioxidants, including ascorbate, were ineffective. alpha, beta-Unsaturated aldehydes (acrolein and crotonaldehyde) in cigarette smoke may react with protein -SH and -NH2 groups by a Michael addition reaction that results in a protein-bound aldehyde functional group. Gas-phase cigarette smoke is capable of converting tyrosine to 3-nitrotyrosine and dityrosine, indicating free radical mechanisms of protein damage by nitrogen oxides. Aldehydes and nitrogen oxides in cigarette smoke may be significant contributors to biomolecular damage, and endogenous antioxidants can attenuate some of these adverse effects.

Aldehydes↗
PubMed1995

Metal ion release from mechanically-disrupted human arterial wall. Implications for the development of atherosclerosis.

Oxidation of low density lipoproteins (LDL) in blood vessel walls plays a significant role in the development of atherosclerosis. LDL oxidation in vitro is greatly accelerated by the presence of "catalytic" iron or copper ions, which have already been shown to be present within advanced atherosclerotic lesions. We demonstrate here that mechanical damage to human arterial wall samples (both normal and early or intermediate atherosclerotic lesions) causes release of "catalytic" iron and copper ions, to an extent increasing with the damage. It may be that traumatic (e.g. during angioplasty) or other injury to the vessel wall contributes to the generation of metal ions that can facilitate LDL oxidation and other free radical reactions, so promoting atherosclerosis.

Arteries↗
PubMed1994

Promotion of oxidative damage to arachidonic acid and alpha 1-antiproteinase by anti-inflammatory drugs in the presence of the haem proteins myoglobin and cytochrome C.

A mixture of myoglobin and hydrogen peroxide (H2O2) causes peroxidation of arachidonic acid. This peroxidation is greatly accelerated by adding phenylbutazone, which is effective even in the absence of H2O2. A wide range of other drugs was examined for their ability to exert similar pro-oxidant effects. We found that meclofenamic acid and flufenamic acid stimulated myoglobin-dependent lipid peroxidation, but only in the presence of H2O2. Ascorbic acid inhibited peroxidation both in the presence and in the absence of these drugs. Phenylbutazone, meclofenamic acid and flufenamic acid could also cause damage to proteins (as measured by inactivation of alpha 1-antiproteinase) in the presence of myoglobin and H2O2. The mitochondrial protein cytochrome c can also stimulate lipid peroxidation in the presence of H2O2. Phenylbutazone and meclofenamic acid, but not flufenamic acid, enhanced the peroxidation, which was again inhibited by ascorbic acid. However, only phenylbutazone caused inactivation of alpha 1-antiproteinase in the presence of cytochrome c and H2O2. Since respiring mitochondria generate superoxide radicals and H2O2, catalysis of lipid peroxidation and of the formation of drug-derived radicals by cytochrome c could be a mechanism contributing to mitochondrial damage by drugs.

Anti-Inflammatory Agents↗
PubMed1994

Intense oxidative DNA damage promoted by L-dopa and its metabolites. Implications for neurodegenerative disease.

Oxidative DNA damage can cause mutation and cell death. We show that L-DOPA, dopamine and 3-O-methyl-DOPA cause extensive oxidative DNA damage in the presence of H2O2 and traces of copper ions. 8-Hydroxyguanine is the major product. Iron ions were much less effective and manganese ions did not catalyse DNA damage. We propose that copper ion release, in the presence of L-DOPA and its metabolites, may be an important mechanism of neurotoxicity, e.g. in Parkinson's disease and amyotrophic lateral sclerosis.

Brain Chemistry↗
PubMed1994

Molecular mechanisms of damage by excess nitrogen oxides: nitration of tyrosine by gas-phase cigarette smoke.

Nitric oxide (nitrogen monoxide, .NO) plays important physiological roles, but an excess can be toxic. .NO is present in cigarette smoke (CS) at up to 500 ppm, and probably represents one of the greatest exogenous sources of .NO to which humans are exposed. We show here that gas-phase CS is capable of converting tyrosine to 3-nitrotyrosine (3-NO2-Tyr) and dityrosine, to an extent dependent on time of exposure and pH. Glutathione, ascorbic acid and uric acid decreased the CS-induced formation of 3-NO2-Tyr and dityrosine. We suggest that nitrogen oxides in CS can modify proteins in the respiratory tract and may contribute to CS toxicity.

Antioxidants↗