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B Halliwell

Publications and source records attributed to B Halliwell.

At least 253 records · Page 14Linked to original sources
PubMed1992

Hydrogen peroxide-induced cardiovascular reflexes. Role of hydroxyl radicals.

Mesenteric ischemia reflexly activates the cardiovascular system. In addition, mesenteric ischemia and reperfusion generate reactive oxygen species. However, the ability of these short-lived reactive oxygen species to generate cardiovascular reflexes is unknown. We therefore investigated cardiovascular reflexes induced by serosal application of hydrogen peroxide (H2O2) to the gallbladder, stomach, or duodenum in anesthetized cats. Serosal application of hydrogen peroxide (44 mumols) to the gallbladder (n = 14) significantly (p less than 0.05) increased mean arterial blood pressure (MAP) by 37 +/- 6 mm Hg, left ventricular dP/dt by 1,893 +/- 416 mm Hg/sec, heart rate by 6 +/- 1 beats per minute, and systemic vascular resistance from 0.34 +/- 0.01 to 0.42 +/- 0.04 peripheral resistance units. The cardiovascular effects were dose-dependent over a range of 0.4 pmol to 132 mumols H2O2. Celiac and superior mesenteric ganglionectomy abolished H2O2-induced cardiovascular effects. Dimethylthiourea (10 mg/kg), a reactive oxygen species scavenger, significantly (p less than 0.05) attenuated 44 mumols H2O2-induced increases in MAP from 36 +/- 3 to 2 +/- 2 mm Hg. Deferoxamine (10 mg/kg) also significantly attenuated 44 mumols H2O2-induced increases in MAP from 40 +/- 7 to 19 +/- 10 mm Hg, but iron-loaded deferoxamine did not. Aspirin (50 mg/kg) did not attenuate H2O2-induced excitation of the cardiovascular system. These data suggest that H2O2 activates abdominal visceral afferents to reflexly stimulate the cardiovascular system by a mechanism involving hydroxyl radicals. Thus, reactive oxygen species could modulate systemic vascular tone by stimulating abdominal visceral afferents during mesenteric ischemia and reperfusion.

Animals↗
PubMed1992

Antioxidant and pro-oxidant properties of active rosemary constituents: carnosol and carnosic acid.

1. Carnosol and carnosic acid have been suggested to account for over 90% of the antioxidant properties of rosemary extract. 2. Purified carnosol and carnosic acid are powerful inhibitors of lipid peroxidation in microsomal and liposomal systems, more effective than propyl gallate. 3. Carnosol and carnosic acid are good scavengers of peroxyl radicals (CCl3O2.) generated by pulse radiolysis, with calculated rate constants of 1-3 x 10(6) M-1 s-1 and 2.7 x 10(7) M-1 s-1 respectively. 4. Carnosic acid reacted with HOCl in such a way as to protect the protein alpha 1-antiproteinase against inactivation. 5. Both carnosol and carnosic acid stimulated DNA damage in the bleomycin assay but they scavenged hydroxyl radicals in the deoxyribose assay. The calculated rate constants for reaction with .OH in the deoxyribose system for carnosol and carnosic acid were 8.7 x 10(10) M-1 s-1 and 5.9 x 10(10) M-1 s-1 respectively. 6. Carnosic acid appears to scavenge H2O2, but it could also act as a substrate for the peroxidase system. 7. Carnosic acid and carnosol reduce cytochrome c but with a rate constant significantly lower than that of O2(-.).

Abietanes↗
PubMed1992

Oxidative damage to human plasma proteins by ozone.

Exposure of human plasma to ozone produces oxidative protein damage, measured as protein carbonyl formation. Isolated human albumin or creatine phosphokinase are oxidized much faster than are total proteins. Consideration must be given to proteins as targets of oxidative injury by ozone in vivo.

Adult↗
PubMed1992

The measurement of oxidative damage to DNA by HPLC and GC/MS techniques.

Oxidative damage to DNA has been measured by quantitating 8-hydroxy-2'-deoxyguanosine (8-OHdGuo) after enzymic digestion of DNA, followed by HPLC separation and electrochemical detection. Alternatively, 8-hydroxyguanine (and a wide range of other base-derived products of free radical attack) may be measured after acidic hydrolysis of DNA or chromatin, followed by derivatization and gas-chromatography/mass spectrometry. Both techniques have comparable sensitivity, but GC/MS enables determination of a wide variety of chemical changes to all four DNA bases and it can be applied to DNA-protein complexes. However, the two techniques do not always give similar results. Potential reasons for this are discussed. Greater attention to methodological questions is required before using measurement of 8-OHdGuo as a "routine" marker of oxidative DNA damage in vivo.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1992

Peroxyl radical scavenging by a series of coumarins.

Sixteen plant-derived or synthetic coumarins with various hydroxyl and other substitutions were tested for their ability to scavenge alkylperoxyl radicals generated in the aqueous phase by the controlled thermolysis of 2,2'-azo-bis-(2-amidinopropane) dihydrochloride (ABAP). Protection by coumarins against inactivation of lysozyme by the radicals was assayed by measuring the loss of turbidity of suspensions of M. lysodeikticus. Ten of the coumarins were potent scavengers of aqueous peroxyl radicals with activities comparable to n-propyl gallate, desferrioxamine, ferrioxamine and trolox c, yielding IC50 values in the range 21 to 92 micromolar. The presence of 6,7-ortho-dihydroxy functions gave compounds of the greatest potency. Scavenging activity was unrelated to ability to chelate iron ions. The active coumarins are attractive candidates for evaluation as protective agents against disorders in which oxidative stress is implicated.

Amidines↗
PubMed1991

Nickel(II)- and cobalt(II)-dependent damage by hydrogen peroxide to the DNA bases in isolated human chromatin.

Nickel compounds are known to be carcinogenic to humans and animals. Cobalt compounds produce tumors in animals and are probably carcinogenic to humans. The mechanisms of the carcinogenicity of these metal compounds, however, have remained elusive. In the present work, we have investigated the ability of Ni(II) and Co(II) ions in the presence of H2O2 to cause chemical changes in DNA bases in chromatin extracted from cultured cells of human origin. Eleven modified DNA bases in chromatin were identified and quantitated by the use of gas chromatography-mass spectrometry. 2-Hydroxyadenine (isoguanine), which has not previously been shown to occur DNA or chromatin, was also identified. Products identified were typical hydroxyl radical-induced products of DNA bases, suggesting that the hydroxyl radical was involved in their formation. This idea was supported by partial inhibition of product formation by typical scavengers of hydroxyl radical. Partial inhibition of product formation indicated a possible "site-specific" formation of hydroxyl radical by unchelated Ni(II) and Co(II) ions bound to chromatin. Although treatment of chromatin for 1 h with Co(II)/H2O2 caused formation of significant amounts of products, treatment with Ni(II)/H2O2 required incubation times of more than 5 h and an increase in Ni(II) concentration before increases in product amounts above background levels became detectable. In both cases, ascorbic acid did not increase product yields. Glutathione at a physiologically relevant concentration had little overall effect on DNA base modification. Superoxide dismutase increased the yields of most products. Chelation of Ni(II) and Co(II) ions with EDTA almost completely inhibited product formation. Ni(II) in the presence of H2O2 produced greater base damage to the DNA in chromatin than to isolated DNA, unlike other metal ions tested. DNA damage in chromatin caused by Ni(II) and Co(II) ions in the presence of H2O2 may contribute to the established genotoxicity and carcinogenicity of these metal ions.

Animals↗
PubMed1991

Inhibition of mammalian 5-lipoxygenase and cyclo-oxygenase by flavonoids and phenolic dietary additives. Relationship to antioxidant activity and to iron ion-reducing ability.

We investigated the ability of various plant flavonoids (a) to inhibit 5-lipoxygenase and cyclooxygenase activities in rat peritoneal leukocytes, (b) to inhibit lipid peroxidation in rat liver microsomes, and (c) to stimulate DNA degradation caused by the antibiotic bleomycin in the presence of ferric ions. These compounds were compared with a range of synthetic phenolic substances including carnosol, vanillin, vitamin E and its analogue trolox c. The flavonoids were potent inhibitors of non-enzymatic peroxidation in membranes but this was not significantly correlated with their ability to inhibit either pathway of eicosanoid synthesis, suggesting that their mode of inhibition of 5-lipoxygenase/cyclooxygenase is not simply due to interception of peroxyl radicals generated at the active site of the enzymes. Many of the flavonoids and other compounds (including carnosol, vitamin E and trolox c) stimulated Fe3+/bleomycin-dependent DNA degradation. Those flavonoids which stimulated DNA degradation at low concentrations but which inhibited it at higher concentrations ("biphasic" effect, possibly caused by changing relative contributions of ability to reduce ferric-bleomycin or to chelate iron ions from the bleomycin) were selective inhibitors of 5-lipoxygenase compared to cyclo-oxygenase. In contrast, those flavonoids that did not stimulate DNA degradation at all proved to be cyclo-oxygenase selective inhibitors. Compounds that increased Fe3+/bleomycin-dependent DNA damage up to a maintained plateau were non-selective inhibitors of both 5-lipoxygenase and cyclo-oxygenase. Thus, a combination of iron-chelating and iron ion-reducing properties appears to be required for selective 5-lipoxygenase inhibition by phenolic compounds. Carnosol, vitamin E and trolox c were also found to be 5-lipoxygenase inhibitors of varying potency, and all were less active as cyclo-oxygenase inhibitors.

Abietanes↗
PubMed1991

Reactive oxygen species in living systems: source, biochemistry, and role in human disease.

Reactive oxygen species are constantly formed in the human body and removed by antioxidant defenses. An antioxidant is a substance that, when present at low concentrations compared to that of an oxidizable substrate, significantly delays or prevents oxidation of that substrate. Antioxidants can act by scavenging biologically important reactive oxygen species (O2-., H2O2.OH, HOCl, ferryl, peroxyl, and alkyl), by preventing their formation, or by repairing the damage that they do. One problem with scavenging-type antioxidants is that secondary radicals derived from them can often themselves do biologic damage. These various principles will be illustrated by considering several thiol compounds.

Antioxidants↗
PubMed1991

Free radical scavenging and inhibition of lipid peroxidation by beta-blockers and by agents that interfere with calcium metabolism. A physiologically-significant process?

It has been proposed that beta-blockers and agents affecting Ca2+ metabolism might exert cardioprotective actions because of their ability to act as antioxidants in vivo. The feasibility of this proposal was tested by examining the reaction of a series of such compounds with various oxygen-derived species. None of the compounds tested was sufficiently reactive with superoxide radical, hydrogen peroxide or hypochlorous acid for scavenging of these species to be feasible in vivo at the drug concentrations present in patients given the usual therapeutic doses. All the drugs tested were powerful scavengers of hydroxyl radical except for flunarizine, which stimulated iron ion-dependent hydroxyl radical generation from hydrogen peroxide. However, none of the drugs significantly inhibited production of hydroxyl radicals in this system. Propranolol, verapamil and flunarizine had significant inhibitory effects on the peroxidation of rat liver microsomes in the presence of iron ions and ascorbic acid. All three compounds exerted weaker inhibitory effects on peroxidation of arachidonic acid caused by a mixture of myoglobin and H2O2: pindolol stimulated peroxidation in this system. It is concluded that the ability of beta-blockers and "Ca(2+)-blockers" to inhibit lipid peroxidation varies with the lipid substrate used and the mechanism by which peroxidation is induced. We conclude that suggestions that beta-blockers and "Ca(2+)-blockers" exert antioxidant effects in vivo are not well founded, although there is a possibility that verapamil and propranolol might have some inhibitory effects against peroxidation if they accumulate in membranes to a sufficiently-high concentration in vivo. We could not confirm the reported ability of propranolol to inhibit the enzyme xanthine oxidase.

Adrenergic beta-Antagonists↗
PubMed1991

Hydroxylation of salicylate by microsomal fractions and cytochrome P-450. Lack of production of 2,3-dihydroxybenzoate unless hydroxyl radical formation is permitted.

Attack by hydroxyl radicals (.OH) upon salicylate (2-hydroxybenzoate) leads to formation of both 2,3-dihydroxybenzoate (2,3-DHB) and 2,5-dihydroxybenzoate (gentisate, 2,5-DHB). It has been suggested that formation of 2,3-DHB from salicylate is a means of monitoring .OH formation. Production of 2,3-DHB and 2,5-DHB by liver microsomal fractions and isoforms of cytochrome P-450 was investigated. Liver microsomes prepared from variously treated rats and rabbits catalysed the formation of 2,5-DHB but not 2,3-DHB. Formation of 2,5-DHB was inhibited by CO, metyrapone and SKF-525A, but not by the .OH scavengers mannitol and formate or by the iron chelator desferrioxamine. Purified P-450s IIE1, IIB4 or IA2 from rabbit liver microsomes, reconstituted together with NADPH-cytochrome P-450 reductase, led to formation of equal amounts of 2,3-DHB and 2,5-DHB in reactions that were almost completely inhibited by mannitol or formate. Addition of Fe3+/EDTA either to microsomes or to membranes containing reconstituted P-450 caused formation of approximately equal amounts of 2,3-DHB and 2,5-DHB, consistent with an .OH-dependent attack on salicylate. The data indicate that the microsomal P-450 system catalyses hydroxylation of salicylate to 2,5-DHB, but not formation of 2,3-DHB. Hence measurement of 2,3-DHB might provide a means of monitoring .OH formation. Care must be taken in studies of substrate hydroxylation by microsomes or reconstituted P-450 systems to avoid artefacts resulting from .OH generation.

Animals↗
PubMed1991

DNA damage by oxygen-derived species. Its mechanism and measurement in mammalian systems.

When cells are exposed to oxidative stress, DNA damage frequently occurs. The molecular mechanisms causing this damage may include activation of nucleases and direct reaction of hydroxyl radicals with the DNA. Several oxygen-derived species can attack DNA, producing distinctive patterns of chemical modification. Observation of these patterns and measurement of some of the products formed has been used to determine the role of different oxygen-derived species in DNA cleavage reactions, to assess the extent of oxidative damage to DNA in vivo and to investigate the mechanism of DNA damage by ionizing radiation and chemical carcinogens.

Animals↗
PubMed1991

Bleomycin-dependent damage to the bases in DNA is a minor side reaction.

The antitumor antibiotic bleomycin degrades DNA in the presence of ferric ions and H2O2 or in the presence of ferric ions, oxygen, and ascorbic acid. When DNA degradation is measured as formation of base propenals by the thiobarbituric acid assay, it is not inhibited by superoxide dismutase and scavengers of the hydroxyl radical or by catalase (except that catalase inhibits in the bleomycin/ferric ion/H2O2 system by removing H2O2). Using the technique of gas chromatography/mass spectrometry with selected-ion monitoring, we show that DNA degradation is accompanied by formation of small amounts of modified DNA bases. The products formed are identical with those generated when hydroxyl radicals react with DNA bases. Base modification is significantly inhibited by catalase and partially inhibited by scavengers of the hydroxyl radical and by superoxide dismutase. We suggest that the bleomycin-oxo-iron ion complex that cleaves the DNA to form base propenals can decompose in a minor side reaction to generate hydroxyl radical, which accounts for the base modification in DNA. However, hydroxyl radical makes no detectable contribution to the base propenal formation.

Ascorbic Acid↗
PubMed1991

Copper-ion-dependent damage to the bases in DNA in the presence of hydrogen peroxide.

Mixtures of Cu2+ and H2O2 at pH 7.4 caused damage to the bases in DNA greater than that caused by mixtures of Fe3+ and H2O2. Addition of ascorbic acid to the Cu2+/H2O2 system caused a very large increase in base damage, much greater than that produced by the Fe3+/H2O2/ascorbic acid system. The products of base damage in the presence of Cu2+ were typical products that have been shown to result from attack of hydroxyl radicals upon the DNA bases. Cytosine glycol, thymine glycol, 8-hydroxyadenine and especially 8-hydroxyguanine were the major products in both the Cu2+/H2O2 and the Cu2+/H2O2/ascorbic acid systems. Base damage in DNA by these systems was inhibited by the chelating agents EDTA and nitrilotriacetic acid and by catalase, but not by superoxide dismutase, nor by the hydroxyl-radical scavenger mannitol. It is proposed that Cu2+ ions bound to the DNA react with H2O2 and ascorbic acid to generate hydroxyl radicals, which then immediately attack the DNA bases in a site-specific manner. A hypoxanthine/xanthine oxidase system also caused damage to the DNA bases in the presence of Cu2+ ions. This was inhibited by superoxide dismutase and catalase. The high activity of Cu2+ ions, when compared with Fe3- ions, in causing hydroxyl-radical-dependent damage to DNA and to other biomolecules, means that the availability of Cu2+ ions in vivo must be carefully controlled.

Copper↗
PubMed1991

The antioxidant action of ergothioneine.

Ergothioneine is a product of plant origin that accumulates in animal tissues. Its suggested ability to act as an antioxidant has been evaluated. Ergothioneine is a powerful scavenger of hydroxyl radicals (.OH) and an inhibitor of iron or copper ion-dependent generation of .OH from hydrogen peroxide (H2O2). It is also an inhibitor of copper ion-dependent oxidation of oxyhaemoglobin, and of arachidonic acid peroxidation promoted by mixtures of myoglobin (or haemoglobin) and H2O2. Ergothioneine is a powerful scavenger of hypochlorous acid, being able to protect alpha 1-antiproteinase against inactivation by this molecule. By contrast, it does not react rapidly with superoxide (O2-) or hydrogen peroxide (H2O2) and it does not inhibit microsomal lipid peroxidation in the presence of iron ions. Overall, our results show that ergothioneine at the concentrations present in vivo could act as an antioxidant.

Animals↗
PubMed1991

Damage to the DNA bases in mammalian chromatin by hydrogen peroxide in the presence of ferric and cupric ions.

Modification of DNA bases in mammalian chromatin upon treatment with hydrogen peroxide in the presence of ferric and cupric ions was studied. Ten DNA base products in mammalian chromatin were identified and quantitated by the use of gas chromatography-mass spectrometry with selected-ion monitoring after hydrolysis of chromatin and trimethylsilylation of hydrolysates. This technique permitted the analysis of modified DNA bases in chromatin without the necessity of isolation of DNA from chromatin first. Modified bases identified were typical hydroxyl radical-induced products of DNA, indicating the involvement of hydroxyl radical in their formation. This was also confirmed by inhibition of product formation by typical scavengers of hydroxyl radical. The inhibition of product formation was much more prominent in the presence of chelated ions than unchelated ions, indicating a possible site-specific formation of hydroxyl radical when metal ions are bound to chromatin. Hydrogen peroxide in the presence of cupric ions caused more DNA damage than in the presence of ferric ions. Chelation of cupric ions caused a marked inhibition in product formation. By contrast, DNA was damaged more extensively in the presence of chelated ferric ions than in the presence of unchelated ferric ions. The presence of ascorbic acid generally increased the yields of the products, indicating increased production of hydroxyl radical by reduction of metal ions by ascorbic acid. Superoxide dismutase afforded partial inhibition of product formation only in the case of chelated iron ions. The yields of the modified bases in chromatin were lower than those observed with calf thymus DNA under the same conditions.

Animals↗
PubMed1991

Evaluation of the ability of the angiotensin-converting enzyme inhibitor captopril to scavenge reactive oxygen species.

Captopril, an inhibitor of angiotensin-converting enzyme, has been suggested to have additional cardioprotective action because of its ability to act as an antioxidant. The rates of reaction of captopril with several biologically-relevant reactive oxygen species were determined. Captopril reacts slowly, if at all, with superoxide (rate constant less than 10(3) M-1 s-1) or hydrogen peroxide (rate constant less than M-1 s-1). It does not inhibit peroxidation of lipids stimulated by iron ions and ascorbate or by the myoglobin/H2O2 system. Indeed, mixtures of ferric ion and captopril can stimulate lipid peroxidation. Captopril reacts rapidly with hydroxyl radical (rate constant greater than 10(9) M-1 s-1) but might be unlikely to compete with most biological molecules for OH because of the low concentration of captopril that can be achieved in vivo during therapeutic use. Captopril did not significantly inhibit iron ion-dependent generation of hydroxyl radicals from hydrogen peroxide. By contrast, captopril is a powerful scavenger of hypochlorous acid: it was able to protect alpha 1-antiproteinase (alpha 1 AP) against inactivation by this species and to prevent formation of chloramines from taurine. We suggest that the antioxidant action of captopril in vivo is likely to be limited, and may be restricted to protection against damage by hypochlorous acid derived from the action of neutrophil myeloperoxidase.

Animals↗