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Biomedical subjects

B Halliwell

Publications and source records attributed to B Halliwell.

At least 73 records · Page 4Linked to original sources
PubMed2000

The gastrointestinal tract: a major site of antioxidant action?

Diets rich in fruits and vegetables delay the onset of many age-related diseases, and contain a complex mixture of antioxidants (including ascorbate, carotenoids, vitamin E and other phenolics such as the flavonoids). However, diet also contains pro-oxidants, including iron, copper, H2O2, haem, lipid peroxides and aldehydes. Nitrite is frequently present in diet, leading to generation of reactive nitrogen species in the stomach. In considering the biological importance of dietary antioxidants, attention has usually focussed on those that are absorbed through the gastrointestinal tract into the rest of the body. In the present paper we develop the argument that the high levels of antioxidants present in certain foods (fruits, vegetables, grains) and beverages (e.g. green tea) play an important role in protecting the gastrointestinal tract itself from oxidative damage, and in delaying the development of stomach, colon and rectal cancer. Indeed, carotenoids and flavonoids do not seem to be as well absorbed as vitamins C and E. Hence their concentrations can be much higher in the lumen of the GI tract than are ever achieved in plasma or other body tissues, making an antioxidant action in the GI tract more likely. Additional protective mechanisms of these dietary constituents (e.g. effects on intercellular communication, apoptosis, cyclooxygenases and telomerase) may also be important.

Animals↗
PubMed2000

Why and how should we measure oxidative DNA damage in nutritional studies? How far have we come?

Free radicals and other reactive species are constantly generated in vivo and cause oxidative damage to DNA at a rate that is probably a significant contributor to the age-related development of cancer. Agents that decrease oxidative DNA damage should thus decrease the risk of cancer development. That is, oxidative DNA damage is a "biomarker" for identifying persons at risk (for dietary or genetic reasons, or both) of developing cancer and for suggesting how the diets of these persons could be modified to decrease that risk. This biomarker concept presupposes that we can measure oxidative damage accurately in DNA from relevant tissues. Little information is available on whether oxidative DNA damage in blood cells mirrors such damage in tissues at risk of cancer development. Measurement of 8-hydroxylated guanine (eg, as 8-hydroxy-2'-deoxyguanosine; 8OHdG) is the commonest method of assessing DNA damage, but there is no consensus on what the true levels are in human DNA. If the lowest levels reported are correct, 8OHdG may be only a minor product of oxidative DNA damage. Indeed, 8OHdG may be difficult to measure because of the ease with which it is formed artifactually during isolation, hydrolysis, and analysis of DNA. Mass spectrometry can accurately measure a wide spectrum of DNA base damage products, but the development of liquid chromatography-mass spectrometry techniques and improved DNA hydrolysis procedures is urgently required. The available evidence suggests that in Western populations, intake of certain fruit and vegetables can decrease oxidative DNA damage, whereas ascorbate, vitamin E, and beta-carotene cannot.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2000

Free radicals and antioxidants in the year 2000. A historical look to the future.

In the late 1950's free radicals and antioxidants were almost unheard of in the clinical and biological sciences but chemists had known about them for years in the context of radiation, polymer and combustion technology. Daniel Gilbert, Rebeca Gerschman and their colleagues related the toxic effects of elevated oxygen levels on aerobes to those of ionizing radiation, and proposed that oxygen toxicity is due to free radical formation, in a pioneering paper in 1956. Biochemistry owes much of its early expansion to the development and application of chromatographic and electrophoretic techniques, especially as applied to the study of proteins. Thus, superoxide dismutase (SOD) enzymes (MnSOD, CuZnSOD, FeSOD) were quickly identified. By the 1980's Molecular Biology had evolved from within biochemistry and microbiology to become a dominant new discipline, with DNA sequencing, recombinant DNA technology, cloning, and the development of PCR representing milestones in its advance. As a biological tool to explore reaction mechanisms, SOD was a unique and valuable asset. Its ability to inhibit radical reactions leading to oxidative damage in vitro often turned out to be due to its ability to prevent reduction of iron ions by superoxide. Nitric oxide (NO.) provided the next clue as to how SOD might be playing a critical biological role. Although NO. is sluggish in its reactions with most biomolecules it is astoundingly reactive with free radicals, including superoxide. Overall, this high reactivity of NO. with radicals may be beneficial in vivo, e.g. by scavenging peroxyl radicals and inhibiting lipid peroxidation. If reactive oxygen species are intimately involved with the redox regulation of cell functions, as seems likely from current evidence, it may be easier to understand why attempts to change antioxidant balance in aging experiments have failed. The cell will adapt to maintain its redox balance. Indeed, transgenic animals over-expressing antioxidants show some abnormalities of function. There must therefore be a highly complex interrelationship between dietary, constitutive, and inducible antioxidants with the body, under genetic control. The challenge for the new century is to be able to understand these relationships, and how to manipulate them to our advantage to prevent and treat disease.

Animals↗
PubMed1999

Free radicals and hearing. Cause, consequence, and criteria.

Reactive oxygen and nitrogen species, including free radicals, are produced in the human body in both health and disease. In health, they may arise as regulatory mechanisms, intercellular signaling species, or as bacteriocidal agents. Their production is normally controlled by the antioxidant defense mechanisms that include intracellular enzymes--for example, glutathione peroxidase and superoxide dismutase--and low molecular-mass compounds such as vitamin E or ascorbic acid. Although repair mechanisms exist, some steady-state basal oxidative damage occurs in all individuals. Oxidative stress arises when there is a marked imbalance between the production and removal of reactive oxygen and nitrogen species. This may originate from an overproduction of these substances or from a depletion in the antioxidant defenses. Certain drugs may induce oxidative stress by forming drug-derived radicals that can not only deplete the antioxidant defenses but can also react directly with biomolecules. To be able to assess whether oxidative stress is occurring in a particular tissue, reliable biomarkers of oxidative damage are required. Since oxidative stress can damage all major biomolecules in vitro and probably in vivo, biomarkers for DNA, protein, and lipid damage are being developed which, when taken with an assessment of the antioxidant status of the individual, will allow evaluation of the involvement of oxidative stress in the etiology of disease and in the side effects of drugs. There is some evidence to suggest that free radical-mediated damage may be involved in the ototoxicity of aminoglycosides and cisplatin derivatives. Whether this is a cause or consequence of the toxic insult to the sensory hair cells of the inner ear remains to be determined.

Aminoglycosides↗
PubMed1999

Tomato consumption modulates oxidative DNA damage in humans.

Consumption of a single serving of tomatoes by healthy human volunteers was sufficient to alter levels of oxidative DNA base damage in white cell DNA within 24 h. Levels of the mutagenic oxidized purine base 8-hydroxyguanine decreased, especially in those subjects whose initial levels of this base were higher than the mean. However, total DNA base damage remained unchanged since levels of 8-hydroxyadenine rose. The ability of tomato consumption to modulate oxidative DNA damage in the short term may indicate why daily consumption of fruits and vegetables is beneficial in decreasing cancer incidence.

DNA↗
PubMed1999

Hydrogen peroxide in human urine: implications for antioxidant defense and redox regulation.

The presence of hydrogen peroxide, at levels sometimes exceeding 100 microM, in human urine samples was established by three different assay methods: 2-oxoglutarate decarboxylation and the ferrous oxidation-xylenol orange (FOX) assay and an oxygen electrode. Detected levels of H(2)O(2) were decreased by addition of superoxide dismutase. We conclude that urine contains autooxidizable molecules that, upon exposure to 21% O(2), undergo rapid superoxide-dependent autooxidation reactions to generate H(2)O(2). The exposure of human tissues to hydrogen peroxide may be greater than is commonly supposed, which has implications in relation to the proposed role of this species in cell signaling.

Adult↗
PubMed1999

Formation and loss of nitrated proteins in peroxynitrite-treated rat skin in vivo.

Peroxynitrite is a reactive cytotoxic species, capable of nitrating tyrosine residues to form 3-nitrotyrosine. Little is known about the formation and loss of nitrated proteins in vivo. We have measured nitrated proteins, by enzyme-linked immunosorbent assay, in rat skin after exposure to peroxynitrite. Peroxynitrite (100-200 nmol site(-1)) was injected into the skin of anesthetized rats. At the highest dose 78.6 +/- 9.5 pmol mg(-1) protein of nitrated BSA equivalents were measured at 4 h and a significant increase was observed for 24 h after administration in skin samples. The loss of nitrated proteins from skin appeared biphasic with an initial (t(1/2) = 2 h) and slower loss (t(1/2) = 22 h). A major nitrated protein was identified as albumin by Western blot analysis. The data demonstrate that a single exposure to peroxynitrite can lead to the presence of nitrated proteins in skin for at least 24 h. The sustained presence of nitrated proteins may influence the inflammatory process in skin disease.

Animals↗
PubMed1999

Oxygen and nitrogen are pro-carcinogens. Damage to DNA by reactive oxygen, chlorine and nitrogen species: measurement, mechanism and the effects of nutrition.

Humans are exposed to many carcinogens, but the most significant may be the reactive species derived from metabolism of oxygen and nitrogen. Nitric oxide seems unlikely to damage DNA directly, but nitrous acid produces deamination and peroxynitrite leads to both deamination and nitration. Scavenging of reactive nitrogen species generated in the stomach may be an important role of flavonoids, flavonoids and other plant-derived phenolic compounds. Different reactive oxygen species produce different patterns of damage to DNA bases, e.g., such patterns have been used to implicate hydroxyl radical as the ultimate agent in H(2)O(2)-induced DNA damage. Levels of steady-state DNA damage in vivo are consistent with the concept that such damage is a major contributor to the age-related development of cancer and so such damage can be used as a biomarker to study the effects of diet or dietary supplements on risk of cancer development, provided that reliable assays are available. Methodological questions addressed in this article include the validity of measuring 8-hydroxydeoxyguanosine (8OHdG) in cellular DNA or in urine as a biomarker of DNA damage, the extent of artifact formation during analysis of oxidative DNA damage by gas chromatography-mass spectrometry and the levels of oxidative damage in mitochondrial DNA.

Antioxidants↗
PubMed1999

Loss of 3-nitrotyrosine on exposure to hypochlorous acid: implications for the use of 3-nitrotyrosine as a bio-marker in vivo.

Peroxynitrite (ONOO-) is a reactive nitrogen species which in vivo is often assessed by the measurement of free or protein bound 3-nitrotyrosine. Indeed, 3-nitrotyrosine has been detected in many human diseases. However, at sites of inflammation there is also production of the powerful oxidant hypochlorous acid (HOCl) formed by the enzyme myeloperoxidase. Low concentrations of HOCl (<30 microM) caused significant and rapid loss (<10 minutes) of free and protein bound 3-nitrotyrosine. In contrast, no loss of 3-nitrotyrosine was observed with hydrogen peroxide, hydroxyl radical, or superoxide generating systems. Therefore, under conditions where there is concomitant peroxynitrite and hypochlorous acid formation, such as at sites of chronic inflammation, it is possible that HOCl removes 3-nitrotyrosine. This may have implications when assessing the role of reactive nitrogen species in disease conditions and could account for some of the discrepancies reported between 3-nitrotyrosine levels in tissues.

Biomarkers↗
PubMed1999

Hypochlorous acid-induced DNA base modification: potentiation by nitrite: biomarkers of DNA damage by reactive oxygen species.

Chronic inflammation results in increased nitric oxide formation and nitrite (NO-2) accumulation. Activated phagocytes release myeloperoxidase generating the cytotoxic agent hypochlorous acid (HOCl). Reaction of HOCl with NO-2 results in the formation of nitryl chloride (NO2Cl), a potent oxidising, nitrating and chlorinating species. Exposure of DNA to NO-2 alone (up to 250 microM) at pH 7.4 did not induce oxidative DNA base damage. However, incubation of DNA with NO-2 in the presence of HOCl led to increases in thymine glycol, 5-hydroxyhydantoin, 8-hydroxyadenine and 5-chlorouracil to levels higher than those achieved by HOCl alone. No significant increases in 8-hydroxyguanine, xanthine, hypoxanthine, 2-hydroxyadenine, FAPy guanine, FAPy adenine and 8-chloroadenine were observed. HOCl-induced depletion of FAPy guanine and 8-hydroxyguanine was reduced in the presence of NO-2. Modification of DNA by HOCl/NO-2 (presumably generating NO2Cl) produces a pattern of DNA base damage products in isolated DNA that is similar to the pattern produced by HOCl but not other reactive species.

Animals↗
PubMed1999

Increased oxidative damage to all DNA bases in patients with type II diabetes mellitus.

Gas chromatography-mass spectrometry was used to measure the oxidative DNA damage in diabetic subjects and controls. Levels of multiple DNA base oxidation products, but not DNA base de-amination or chlorination products, were found to be elevated in white blood cell DNA from patients with type II diabetes as compared with age-matched controls. The chemical pattern of base damage is characteristic of that caused by an attack on DNA by hydroxyl radical. An increased formation of the highly reactive hydroxyl radical could account for many of the reports of oxidative stress in diabetic subjects. There was no evidence of an increased DNA damage by reactive nitrogen or chlorine species.

Base Pairing↗
PubMed1999

Inhibition of peroxynitrite dependent DNA base modification and tyrosine nitration by the extra virgin olive oil-derived antioxidant hydroxytyrosol.

Hydroxytyrosol is one of the o-diphenolic compounds in extra virgin olive oil and has been suggested to be a potent antioxidant. The superoxide radical (O2*-) and nitric oxide (NO*) can react very rapidly to form peroxynitrite (ONOO ), a reactive tissue damaging species thought to be involved in the pathology of several chronic diseases. Hydroxytyrosol was highly protective against the peroxynitrite-dependent nitration of tyrosine and DNA damage by peroxynitrite in vitro. Given that extra virgin olive oil is consumed daily by many humans, hydroxytyrosol derived from this diet could conceivably provide a defense against damage by oxidants in vivo. The biological activity of hydroxytyrosol in vivo will depend on its intake, uptake and access to cellular compartments.

Animals↗
PubMed1999

alpha-Lipoic acid decreases oxidative stress even in diabetic patients with poor glycemic control and albuminuria.

In the present cross-sectional study, the influence of alpha-lipoic acid on markers of oxidative stress, assessed by measurement of plasma lipid hydroperoxides (ROOHs), and on the balance between oxidative stress and antioxidant defence, determined by the ratio ROOH/(alpha-tocopherol/cholesterol), was examined in 107 patients with diabetes mellitus. Patients receiving alpha-lipoic acid (600 mg/day for > 3 months) had significant lower ROOHs and a lower ROOH/(alpha-tocopherol/cholesterol) ratio than those without alpha-lipoic acid treatment [ROOH: 4.76 +/- 2.49 vs. 7.16 +/- 3.22 mumol/l; p < .0001] and [ROOH/(alpha-tocopherol/cholesterol): 1.37 +/- 0.72 vs. 2.16 +/- 1.17; p < 0.0001]. In addition, the influence of glycemic control and albuminuria on ROOHs and on the ratio of ROOH/(alpha-tocopherol/cholesterol) was examined in the presence and absence of alpha-lipoic acid treatment. Patients were subdivided into three groups based on (1) their HbA1 levels (< 7.5, 7.5-9.5, and > 9.5%) and (2) their urinary albumin concentrations (< 20, 20-200, and > 200 mg/l). Neither poor glycemic control, nor the presence of micro- or macroalbuminuria prevented the antioxidant effect of alpha-lipoic acid. Using stepwise multiple regression analysis, alpha-lipoic acid was found to be the only factor significantly predicting low ROOHs and a low ratio of ROOH/(alpha-tocopherol/cholesterol). These data provide evidence that treatment with alpha-lipoic acid improves significantly the imbalance between increased oxidative stress and depleted antioxidant defence even in patients with poor glycemic control and albuminuria.

Albuminuria↗
PubMed1999

The neuronal toxicity of sulfite plus peroxynitrite is enhanced by glutathione depletion: implications for Parkinson's disease.

In Parkinson's disease (PD) and incidental Lewy body disease glutathione levels in the substantia nigra are decreased by 40-50%. Both peroxynitrite (ONOO ) and alterations in the metabolism of sulfur-containing amino acids have been implicated in PD and we have previously shown that sulfite and ONOO- exert synergistic toxicity to a neuronal cell line. This article presents data to show that this synergistic toxicity of sulfite and ONOO- is greatly enhanced by 50% depletion of cellular glutathione levels. The toxicity of sulfite is also slightly enhanced. Neurones with decreased glutathione may be at increased risk from sulfite and especially from the synergistic damaging effects of ONOO- and sulfite. Because sulfite is present normally in the brain as a product of cysteine metabolism, and because increased ONOO- formation has been reported in PD, these events might contribute to neuronal cell death.

Animals↗