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Biomedical subjects

B Halliwell

Publications and source records attributed to B Halliwell.

At least 217 records · Page 12Linked to original sources
PubMed1993

Carcinogenic antioxidants. Diethylstilboestrol, hexoestrol and 17 alpha-ethynyloestradiol.

The synthetic oestrogens diethylstilboestrol, hexoestrol and 17 alpha-ethynyloestradiol are known to be carcinogenic, yet they all exert antioxidant properties in vitro in that they are good inhibitors of iron ion-dependent lipid peroxidation. In rat liver microsomes incubated with Fe(III)-ascorbate or Fe(III)-ADP/NADPH and also in ox-brain phospholipid liposomes incubated with Fe(III)-ascorbate; the overall order of effectiveness of the compounds tested as inhibitors of lipid peroxidation was diethylstilboestrol > hexoestrol > 17 alpha-ethynyloestradiol > 4-hydroxytamoxifen > 17 beta-oestradiol > tamoxifen. Compounds acting as antioxidants towards lipids may also exert pro-oxidant effects towards other molecules such as DNA and thus must never be assumed to be safe for human use.

Animals↗
PubMed1993

Reduction of the surface-tension-lowering ability of surfactant after exposure to hypochlorous acid.

The reactive species hypochlorous acid (HOCl/OCl-) is a major product of the respiratory burst in activated neutrophils. We studied the effects of HOCl/OCl- on human surfactant and upon surfactants Survanta, KL4 and Exosurf, utilizing a pulsating surfactometer for measuring surface tension. HOCl/OCl- induced a marked dose-dependent decrease in the surface-tension-lowering activity of human surfactant. The surfactant containing surfactant proteins B and C (Survanta) was less sensitive; however, synthetic surfactants with or without peptides were not affected by HOCl/OCl- (KL4, Exosurf). Ascorbic acid and GSH protected human surfactant against inactivation by HOCl/OC1-. We suggest that HOCl/OCl- produced by activated phagocytes in the alveolar compartment of the lung could damage endogenous surfactant and affect the function of exogenously administered natural or other surfactants, especially if ascorbic acid and GSH levels in the lung lining fluids are subnormal, as is known to be the case in some inflammatory lung diseases.

Amniotic Fluid↗
PubMed1993

Tamoxifen and related compounds decrease membrane fluidity in liposomes. Mechanism for the antioxidant action of tamoxifen and relevance to its anticancer and cardioprotective actions?

Tamoxifen and related compounds decrease membrane fluidity in ox-brain phospholipid liposomes: their order of effectiveness is, 4-hydroxytamoxifen > 17 beta-oestradiol > tamoxifen > cis-tamoxifen > N-desmethyltamoxifen > cholesterol. A good positive correlation was demonstrated between the decrease in membrane fluidity by these compounds and their antioxidant ability as inhibitors of liposomal and microsomal lipid peroxidation (correlation coefficient, r = 0.99, P < 0.001, in both cases). The ability of tamoxifen to decrease membrane fluidity is suggested to be the mechanism of its antioxidant action and is discussed in relation to its anticancer and cardioprotective actions.

Animals↗
PubMed1993

Enhancement by tamoxifen of the membrane antioxidant action of the yeast membrane sterol ergosterol: relevance to the antiyeast and anticancer action of tamoxifen.

The anticancer drug tamoxifen inhibits lipid peroxidation in ox-brain phospholipid liposomes, and is a good antiyeast agent, with clinical potential. We now report that the ergosterol-containing lipid fraction derived from yeast microsomal membranes (and the ergosterol separated from it) inhibited lipid peroxidation when introduced into ox-brain phospholipid liposomes. Inhibition of lipid peroxidation by the lipid fraction was greatly enhanced when yeast cell growth was inhibited with tamoxifen prior to lipid extraction. The ability of tamoxifen to enhance the membrane antioxidant ability of ergosterol is expressed in terms of a tamoxifen enhancement coefficient. Enhancement by tamoxifen of the membrane antioxidant action of ergosterol is discussed in relation to the antifungal and anticancer actions of tamoxifen.

Animals↗
PubMed1993

Protective actions of tamoxifen and 4-hydroxytamoxifen against oxidative damage to human low-density lipoproteins: a mechanism accounting for the cardioprotective action of tamoxifen?

Tamoxifen and 4-hydroxytamoxifen protect isolated human low-density lipoproteins (LDLs) against copper-ion-dependent lipid peroxidation: 4-hydroxytamoxifen is more protective than tamoxifen or 17 beta-oestradiol. 4-Hydroxytamoxifen and 17 beta-oestradiol also prevent the increase in the electrophoretic mobility of LDL caused by exposure to copper ions, presumably by protection of the apoprotein B of LDL against oxidative modification. Our observations may help to account for the cardioprotective benefits reported to be associated with tamoxifen therapy and prophylaxis in breast cancer.

Copper↗
PubMed1993

Tamoxifen inhibits lipid peroxidation in cardiac microsomes. Comparison with liver microsomes and potential relevance to the cardiovascular benefits associated with cancer prevention and treatment by tamoxifen.

Tamoxifen and 4-hydroxytamoxifen were both good inhibitors of iron-dependent lipid peroxidation in rat cardiac microsomes. Tamoxifen was also a good inhibitor of lipid peroxidation in liposomes prepared from the phospholipid obtained from rat liver microsomes. In a modified rat liver microsomal system containing a sufficiently low amount of peroxidizable phospholipid to make it comparable with the rat cardiac microsomal system, tamoxifen and 4-hydroxytamoxifen were of similar effectiveness as in the cardiac system. Tamoxifen is known to lower serum cholesterol levels, and the findings reported here indicate that the drug might also protect heart cell membranes against peroxidative damage. Potential cardioprotective and antiatherosclerotic benefits of tamoxifen are discussed in relation to the drug's use in cancer prevention and treatment.

Animals↗
PubMed1993

Lipids and oxidised lipids in human atheroma and normal aorta.

Lipids and oxidised lipids were analysed by GC and GC-MS in samples of human atheroma (necrotic gruel from the interior of advanced atherosclerotic plaques in the aorta) and human normal aorta (lesion-free intima plus inner media) from necropsy subjects. Cholest-5-en-3 beta,26-diol and cholest-5-en-3 beta,7 beta-diol were detected in all the atheroma samples examined but not in significant amounts in normal aorta. In atheroma, cholest-5-en-3 beta,26-diol was approximately proportional to cholesterol. Several isomeric hydroxy-octadecadienoic acids were detected in atheroma, and, in smaller amounts, in normal aorta. Many of the components of atheroma showed a high degree of cross-correlation on linear regression analysis, whilst cross-correlations were somewhat weaker for normal aorta. Atheroma showed a vast accumulation of lipid, especially cholesterol, in comparison to normal aorta. The atheroma samples contained a larger proportion of linoleate relative to oleate than the normal aorta. Levels of fatty acids relative to cholesterol were lower for atheroma than for normal aorta. The chemical composition of atheroma appeared unrelated to the age of the subject, whereas age-related increases in linoleate, oleate and cholesterol content were seen in the samples of normal aorta.

Age Factors↗
PubMed1993

Effects of the synthetic anti-oxidant, probucol, on the U937 monoblastoid cell line.

Probucol is a clinically important drug that decreases plasma cholesterol in humans and has a marked anti-atherogenic effect in hyperlipidaemic Watanabe rabbits. The action of probucol in this animal model has been partly attributed to its anti-oxidant abilities. Probucol can decrease the oxidative modification of low-density lipoprotein and hence diminish its uptake by macrophages. In this paper, we have examined the effect of probucol on the monoblastic cell line U937 and on U937 cells induced to differentiate towards a macrophage phenotype by 1,25-dihydroxycholecalciferol (DHCC), tumour necrosis factor-alpha (TNF-alpha) or phorbol myristate acetate (PMA). We found that probucol enhanced the proliferation of undifferentiated U937 cells. Probucol also enhanced proliferation in cultures that had been pre-treated with DHCC or TNF-alpha, but had no effect on cultures that had been pre-treated with PMA. In contrast, when U937 cells were treated simultaneously with probucol and DHCC or TNF-alpha, there was a more marked decrease in proliferation than was induced by these agents in the absence of probucol. Probucol had little effect on the phenotype of resultant cells. The surface expression of CD13 (aminopeptidase N), CD4, CD35 (C3b receptor), CD64 (Fc gamma RI), CD71 (transferrin receptor) and HLA Class II was not affected by probucol. Probucol treatment led to a small increase in the surface expression of CD16 (Fc gamma RIII) in TNF-alpha treated cells and to a small decrease in the expression of CD14 (a monocyte marker) in PMA-treated cells. The induction of c-fgr mRNA and TNF-alpha mRNA by DHCC or PMA or TNF-alpha was not significantly altered in the presence of probucol. The affect of probucol on U937 cells does not appear to be due to its anti-oxidant abilities because butylated hydroxytoluene (BHT), an equally powerful anti-oxidant, did not have the same effect on the cell proliferation as probucol and because no changes were detected in the levels of lipid peroxidation in U937 cell culture supernatants.

Antigens, Surface↗
PubMed1993

Lipid peroxidation: its mechanism, measurement, and significance.

An increased concentration of end products of lipid peroxidation is the evidence most frequently quoted for the involvement of free radicals in human disease. However, it is likely that increased oxidative damage occurs in most, if not all, human diseases and plays a significant pathological role in only some of them. For example, peroxidation appears to be important in atherosclerosis and in worsening the initial tissue injury caused by ischemic or traumatic brain damage. Oxidative stress can damage many biological molecules; indeed, proteins and DNA are often more significant targets of injury than are lipids, and lipid peroxidation often occurs late in the injury process. Many assays are available to measure lipid peroxidation, but no single assay is an accurate measure of the whole process. Application of simple diene-conjugate and thiobarbituric acid (TBA) assays to human tissues and body fluids can produce artifacts. An HPLC-based TBA test can eliminate some of these artifacts.

Arteriosclerosis↗
PubMed1993

The role of oxygen radicals in human disease, with particular reference to the vascular system.

Free radicals, such as superoxide, hydroxyl and nitric oxide, and other reactive oxygen species (ROS), such as hydrogen peroxide, are formed in vivo. Imbalance between production of ROS and anti-oxidant defence can result in oxidative stress, which may arise either from deficiencies of anti-oxidants (such as glutathione, ascorbate or alpha-tocopherol) and/or from increased formation of ROS. Oxidative stress can result in glutathione depletion, lipid peroxidation, membrane damage and DNA strand breaks as well as activation of proteases, nucleases and protein kinases. Some degree of oxidative stress occurs in most, if not all, human diseases, and the major question to be answered is whether it makes a significant contribution to the disease pathology. In the case of atherosclerosis, evidence from studies with the chain-breaking anti-oxidant probucol and from epidemiological work suggests that oxidative damage does indeed make an important contribution to plaque development.

Antioxidants↗
PubMed1993

Use of aromatic hydroxylation of phenylalanine to measure production of hydroxyl radicals after myocardial ischemia in vivo. Direct evidence for a pathogenetic role of the hydroxyl radical in myocardial stunning.

A pathogenetic role of .OH in myocardial stunning has been inferred from the protective effects of .OH scavengers and iron chelators. However, conclusive demonstration of the .OH radical hypothesis of myocardial stunning requires direct verification of three major, but still unproven, assumptions: (1) .OH is produced in the stunned myocardium in vivo; (2) antioxidant therapy inhibits .OH production; and (3) such inhibition results in enhanced recovery of contractility (ie, .OH is necessary for the development of myocardial stunning). Since phenylalanine (Phe) reacts with .OH to form the hydroxylated products ortho-, meta-, and para-tyrosines (o-, m-, and p-tyr), we used aromatic hydroxylation of Phe to detect .OH formation in the stunned myocardium. Open-chest dogs undergoing a 15-minute coronary occlusion followed by reperfusion received an intravenous infusion of Phe (54.3 mg/kg for 11.5 minutes beginning 90 seconds before reperfusion); these animals were given either no antioxidant therapy (group I, n = 15), N-2-mercaptopropionyl glycine (MPG) (group II, n = 11), or MPG combined with superoxide dismutase, catalase, and desferrioxamine (group III, n = 12). In addition, group IV (nonischemic control group, n = 6) received Phe but did not undergo coronary occlusion, whereas group V (ischemic control group, n = 16) underwent a 15-minute occlusion but did not receive Phe or antioxidants. The plasma concentrations of tyrosines in the local venous effluent and in the arterial blood were measured with high-performance liquid chromatography. In group I, production of o- and m-tyr, which are specific markers of .OH formation, began during coronary occlusion but increased dramatically immediately after reperfusion, peaking at 1 minute and continuing up to 10 minutes of reperfusion. In group II, the production of o- and m-tyr was markedly decreased throughout the first 10 minutes of reperfusion. In group III, the production of m-tyr was decreased to levels similar to those in group II, whereas the production of o-tyr was almost completely abolished. There was no appreciable production of o- or m-tyr in group IV. Recovery of contractile function (assessed as systolic wall thickening) was increased in group I vs group V. Recovery of function was further enhanced in group II, with only a slight additional improvement in group III.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Lipid peroxidation in hyperlipidaemic patients. A study of plasma using an HPLC-based thiobarbituric acid test.

The question of "increased lipid peroxidation" in plasma from hyperlipidaemic patients was investigated using an improved HPLC-based assay for thiobarbituric acid-reactive material. Levels of TBARS in healthy human controls were at or close to zero, provided that butylated hydroxytoluene was added to the sample with the TBA reagents. Levels of plasma TBARS in hyperlipidaemic patients were elevated, although the absolute levels were much lower than those reported previously in the literature.

Adult↗
PubMed1993

Evaluation of the antioxidant actions of ferulic acid and catechins.

We have evaluated the abilities of ferulic acid, (+/-) catechin, (+) catechin and (-) epicatechin to scavenge the reactive oxygen species hydroxyl radical (OH.), hypochlorous acid (HOCl) and peroxyl radicals (RO2.). Ferulic acid tested at concentrations up to 5 mM inhibited the peroxidation of phospholipid liposomes. Both (+/-) and (+) catechin and (-) epicatechin were much more effective. All the compounds tested reacted with trichloromethyl peroxyl radical (CCl3 O2.) with rate constants > 1 x 10(6) M-1 s-1. A mixture of FeCl3-EDTA, hydrogen peroxide (H2O2) and ascorbic acid at pH 7.4, has often been used to generate hydroxyl radicals (OH.) which are detected by their ability to cause damage to the sugar deoxyribose. Ferulic acid, (+) and (+/-) catechin and (-) epicatechin inhibited deoxyribose damage by reacting with OH. with rate constants of 4.5 x 10(9)M-1 s-1, 3.65 x 10(9) M-1 s-1, 2.36 x 10(9) M-1 s-1 and 2.84 x 10(9) M-1 s-1 respectively. (-) Epicatechin, ferulic acid and the (+) and (+/-) catechins exerted pro-oxidant action, accelerating damage to DNA in the presence of a bleomycin-iron complex. On a molar basis, ferulic acid was less effective in causing damage to DNA compared with the catechins. A mixture of hypoxanthine and xanthine oxidase generates O2-. which reduces cytochrome c to ferrocytochrome c. (+) Catechin and (-) epicatechin inhibited the reduction of cytochrome c in a concentration dependent manner. Ferulic acid and (+/-) catechin had only weak effects. All the compounds tested were able to scavenge hypochlorous acid at a rate sufficient to protect alpha-1-antiproteinase against inactivation. Our results show that catechins and ferulic acid possess antioxidant properties. This may become important given the current search for "natural" replacements for synthetic antioxidant food additives.

Antioxidants↗