Ebselen as a glutathione peroxidase mimic and as a scavenger of peroxynitrite.
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Animals↗
Biomedical subjects
H Sies
Publications and source records attributed to H Sies.
Lycopene is more bioavailable from tomato paste than from fresh tomatoes.
Lycopene bioavailability from a single dose of fresh tomatoes or tomato paste (23 mg lycopene) ingested together with 15 g corn oil was compared by analyzing carotenoid concentrations in the chylomicron fraction. The lycopene isomer pattern was the same in both fresh tomatoes and tomato paste. The triacylglycerol response in chylomicrons was not significantly different after both treatments. Ingestion of tomato paste was found to yield 2.5-fold higher total and all-trans-lycopene peak concentrations (P < 0.05 and P < 0.005, respectively) and 3.8-fold higher area under the curve (AUC) responses (P < 0.001) than ingestion of fresh tomatoes. The same was calculated for lycopene cis-isomers, but only the AUC response for the cis-isomers was significantly higher after ingestion of tomato paste (P < 0.005). No difference was observed in the alpha- and beta-carotene response. Thus, in humans, the bioavailability of lycopene is greater from tomato paste than from fresh tomatoes.
Adult↗
Biological activities of natural and synthetic carotenoids: induction of gap junctional communication and singlet oxygen quenching.
Induction of gap junctional communication (GJC) and antioxidant activities of carotenoids have been considered as biochemical mechanisms underlying the cancer-preventive properties of these compounds. beta-Carotene and other carotenoids, including those lacking provitamin A activity, proved to be active in both these parameters. The beta-carotene analogs retrodehydro-beta-carotene, echinenone, cryptoxanthin (3-hydroxy-beta-carotene), 4-hydroxy-beta-carotene and canthaxanthin stimulate GJC and efficiently deactivate singlet molecular oxygen. beta-Carotene is less active than its retro-dehydro analog with respect to (1)O2-quenching but GJC is similar. The five-membered ring analog of canthaxanthin, dinor-canthaxanthin, has less effect on GJC as compared with the parent compound but exhibits increased singlet oxygen quenching. Straight-chain polyene dialdehydes are quenchers of singlet oxygen, the efficiency increasing with the number of conjugated double bonds. However, none of these compounds significantly induce GJC. These data indicate that the two properties of carotenoids addressed in this study may operate independent of each other.
Antioxidants↗
Increased frequency of a null-allele for NAD(P)H: quinone oxidoreductase in patients with urological malignancies.
The NQO1 locus on chromosome 16q2.2 encodes NAD(P)H:quinone oxidoreductase, an enzyme implicated in detoxication and protection against redox cycling. Two alleles have been identified in the human population, the rarer one, termed the null-allele, coding for a nonfunctional enzyme. Since lack of NQOR activity has been suggested to increase susceptibility to certain cancers, the distribution of the two alleles was determined by polymerase chain reaction-restriction fragment length polymorphism analysis in patients with renal cell carcinoma (n = 131) and urothelial carcinoma (n = 99) compared with a normal population (n = 260). Allele distribution in the normal population followed a Hardy-Weinberg distribution with frequencies of 0.867 for the major allele and 0.133 for the null-allele. Increased frequencies of the null-allele were found in the tumour patient groups (0.191 and 0.182, respectively) due to an increased number of both homo- and heterozygotes. The odds ratios for homozygous null-allele vs. wild-type genotypes were 1.7 and 3.6 for renal cell carcinoma and urothelial carcinoma, respectively. These data are compatible with the assumption that diminished activity of NQOR in some individuals increases susceptibility to certain cancers.
Alleles↗
Oxidative stress: oxidants and antioxidants.
An imbalance between oxidants and antioxidants in favour of the oxidants, potentially leading to damage, is termed 'oxidative stress'. Oxidants are formed as a normal product of aerobic metabolism but can be produced at elevated rates under pathophysiological conditions. Antioxidant defense involves several strategies, both enzymatic and non-enzymatic. In the lipid phase, tocopherols and carotenes as well as oxy-carotenoids are of interest, as are vitamin A and ubiquinols. In the aqueous phase, there are ascorbate, glutathione and other compounds. In addition to the cytosol, the nuclear and mitochondrial matrices and extracellular fluids are protected. Overall, these low molecular mass antioxidant molecules add significantly to the defense provided by the enzymes superoxide dismutase, catalase and glutathione peroxidases.
Animals↗
Porphyrins preferentially accumulate in a melanoma following intravenous injection of 5-aminolevulinic acid.
Systemically, as opposed to topically, administered 5-aminolevulinic acid (ALA) is of increasing interest for photodynamic therapy (PDT) because of more selective and more homogeneous accumulation of porphyrins in neoplastic tissues. This study investigates the profile and the time course of porphyrin metabolites in various tissues following intravenous injection of ALA (0.5 g/kg body weight) into hamsters bearing an amelanotic melanoma (A-Mel-3). ALA injection led to maximum levels of ALA and porphyrins in erythrocytes after 45 min. In tissues, maximum porphyrin levels were detected after 45 min (tumor), 4 h (skin, kidney), and 24 h (liver). Sixfold higher porphyrin levels were observed in tumors as compared to surrounding normal skin at 45 min. Predominant porphyrin metabolites were protoporphyrin (tumor, skin, liver, kidney), coproporphyrin (tumor) and highly carboxylated porphyrins (tumor, skin, kidney). These data suggest optimum efficacy of light irradiation in systemic PDT with ALA within the first two hours after injection. Tumor-specific ALA metabolism yields protoporphyrin and coproporphyrin as the prevailing porphyrin metabolites.
Aminolevulinic Acid↗
Antioxidant defense: vitamins E and C and carotenoids.
Reactive oxygen species are thought to be implicated in the pathogenesis of various human diseases. They are generated endogenously under physiological and pathological conditions but also upon exposure to exogenous challenge. The organism maintains defense systems against reactive oxygen species, including enzymes and low-molecular-weight antioxidants. Important antioxidants such as vitamins E and C and carotenoids are provided from the diet. Vitamin E, as the major chain-breaking antioxidant, inhibits lipid peroxidation, thus preventing membrane damage and modification of low-density lipoproteins. It is regenerated by the water-soluble vitamin C. Carotenoids efficiently scavenge singlet molecular oxygen and peroxyl radicals. There is increasing evidence from epidemiological studies, animal experiments, and in vitro investigations that an increased intake of antioxidants is associated with a diminished risk for several diseases.
Animals↗
Vitamin E improves the aminotransferase status of patients suffering from viral hepatitis C: a randomized, double-blind, placebo-controlled study.
UNLABELLED: Vitamin E has been shown to protect against liver damage induced by oxidative stress in animal experiments. Based on our previous findings of diminished vitamin E levels in patients suffering from viral hepatitis, we treated 23 hepatitis C patients refractory to alpha-interferon therapy with high doses of vitamin E (2 x 400 IU RRR-alpha-tocopherol/day) for 12 weeks. STUDY DESIGN: pro-spective randomized double-blind crossover design. Clinical parameters including alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined for monitoring the disease state, in parallel vitamin E plasma levels and plasma lipids were determined. The plasma levels of the alpha-tocopherol were increased about 2-fold in all 23 patients. In 11 of 23 patients the clinical parameters indicative of liver damage were improved during the phase of vitamin E treatment (48% responders). ALT levels in responders were lowered by 46% and AST levels were lowered by 35% after 12 weeks of vitamin E treatment. Cessation of vitamin E treatment was followed by a rapid relapse of ALT and AST elevation, whereas retreatment led to a reproducible ALT decrease by 45% and AST decrease of 37% after a 6 months followup. Since vitamin E is non-toxic even at elevated doses ingested over extended periods, we suggest the treatment of patients refractory to alpha-interferon therapy suffering from hepatitis C with vitamin E as a supportive therapy.
Alanine Transaminase↗
The reaction of peroxynitrite with tert-butyl hydroperoxide produces singlet molecular oxygen.
Peroxynitrite, a biological oxidant, can induce lipid peroxidation in biological membranes which leads to the formation of various hydroperoxides. Here, we report the formation of singlet oxygen (1O2) in the reaction of peroxynitrite with tert-butyl hydroperoxide (t-BOOH) used as a model compound for organic hydroperoxides. The formation of singlet oxygen was observed by (i) dimol emission in the red spectral region, (ii) monomol emission in the infrared region at 1270 nm and by (iii) chemical trapping of singlet oxygen with anthracene-9,10-diyldiethyl disulfate (EAS). The emission signal was increased when H2O was replaced by deuterium oxide and was quenched by sodium azide. When singlet oxygen was generated in the reaction of peroxynitrite with t-BOOH, the 1O2 quenching rate constant for sodium azide was estimated from a Stern-Volmer plot as 1.3 x 10(8) M(-1) S(-1) which is in line with known values. The 1O2 generation in the peroxynitrite/t-BOOH reaction was also detected by the formation of the endoperoxide of EAS. These data establish the generation of 1O2 in the reaction of peroxynitrite with t-BOOH and suggest a potential involvement of 1O2 in peroxynitrite-mediated reactions in biological systems.
Deuterium Oxide↗
Carotenoids and intercellular communication via gap junctions.
Stimulation of gap junctional communication has been suggested to be one of the biochemical mechanisms underlying the cancer-preventive activity of carotenoids. The stimulatory activity is associated with structural properties of the carotenoids. It appears that the presence of a six-membered ring substituent at the end of the conjugated system of double bonds is required for the effects; five-membered ring carotenoids are less active. There is increasing evidence that oxidation products of carotenoids, especially retinoic acid analogs, significantly contribute to this biological property.
Animals↗
Toxic and signaling effects of photochemically or chemically generated singlet oxygen in biological systems.
Singlet oxygen, generated photochemically or chemically, has damaging effects on biomolecules and exerts genotoxic, virucidal and cytotoxic effects. This is of relevance for biological systems because singlet oxygen can be produced photochemically as a result of the irradiation of endogenous or exogenously applied photosensitizers with visible or ultraviolet light, or in dark reactions, e.g. by stimulated phagocytes during the so-called oxidative burst. In addition, there is increasing evidence that singlet oxygen has pronounced effects on cellular signaling events leading to the induced expression of a variety of proteins. A novel observation is the activation of transcription factor AP-2 and cellular signaling cascades comprising the activation of c-Jun-N-terminal kinases (JNK/SAPK) and the NF-kappaB system.
Antiviral Agents↗
Hypochlorite destroys carotenoids in low density lipoproteins thus decreasing their resistance to peroxidative modification.
The effects of hypochlorite (HOCl/OCl-) on the content of carotenoids (trans-lycopene, 5-cis-lycopene, alpha- and beta-carotene) and oxycarotenoids (lutein, zeaxanthin, trans- and cis-2',3'-anhydrolutein, alpha-and beta-cryptoxanthin) in human blood low-density lipoproteins (LDL) were compared using HPLC. Hypochlorite decreased the content of all the above-mentioned pigments in LDL. However, it was more reactive towards carotenoids rather than to their oxy derivatives. The ability of carotenoids and oxycarotenoids to scavenge HOCl/OCl- decreases in the series: trans-lycopene approximately 5-lycopene > alpha-carotene > beta-carotene > zeaxanthin > alpha-cryptoxanthin > cis-2',3'-anhydrolutein > beta-cryptoxanthin > trans-2',3'-anhydrolutein > lutein. Preincubation of LDL with hypochlorite decreased their resistance to CU(2+)-induced accumulation of dienic conjugates that are produced in the course of lipid peroxidation. The data suggest that hypochlorite-induced destruction of carotenoids in LDL decreases their resistance to oxidative modification, thus promoting the development of early stages of atherosclerosis.
Arteriosclerosis↗
Activation of transcription factor AP-2 mediates UVA radiation- and singlet oxygen-induced expression of the human intercellular adhesion molecule 1 gene.
UVA radiation is the major component of the UV solar spectrum that reaches the earth, and the therapeutic application of UVA radiation is increasing in medicine. Analysis of the cellular effects of UVA radiation has revealed that exposure of human cells to UVA radiation at physiological doses leads to increased gene expression and that this UVA response is primarily mediated through the generation of singlet oxygen. In this study, the mechanisms by which UVA radiation induces transcriptional activation of the human intercellular adhesion molecule 1 (ICAM-1) were examined. UVA radiation was capable of inducing activation of the human ICAM-1 promoter and increasing ICAM-1 mRNA and protein expression. These UVA radiation effects were inhibited by singlet oxygen quenchers, augmented by enhancement of singlet oxygen life-time, and mimicked in unirradiated cells by a singlet oxygen-generating system. UVA radiation as well as singlet oxygen-induced ICAM-1 promoter activation required activation of the transcription factor AP-2. Accordingly, both stimuli activated AP-2, and deletion of the putative AP-2-binding site abrogated ICAM-1 promoter activation in this system. This study identified the AP-2 site as the UVA radiation- and singlet oxygen-responsive element of the human ICAM-1 gene. The capacity of UVA radiation and/or singlet oxygen to induce human gene expression through activation of AP-2 indicates a previously unrecognized role of this transcription factor in the mammalian stress response.
Cell Line↗
Kinetic study of the reaction of ebselen with peroxynitrite.
The second-order rate constant for the reaction of ebselen with peroxynitrite (ONOO-) is (2.0+/-0.1) X 10(6) M(-1) s(-1) at pH > or = 8 and 25 degrees C, 3-4 orders of magnitude higher than the rate constants observed for cysteine, ascorbate, or methionine. The activation energy is relatively low, 12.8 kJ/mol. This is the fastest reaction of peroxynitrite observed so far. It may allow Se-containing compounds to play a novel role in the defense against peroxynitrite, one of the important reactive species generated during inflammatory processes.
Anti-Inflammatory Agents, Non-Steroidal↗
Lycopene: a biologically important carotenoid for humans?
Lycopene is a carotenoid present in human blood (approximately 0.5 micromol/liter plasma), and the tissue levels vary from 1 nmol/g wet wt in adipose tissue to up to 20 nmol/g wet wt in adrenals and testes. Its biological activities include antioxidant activity (singlet oxygen quenching and peroxyl radical scavenging), induction of cell-cell communication, and growth control, but no provitamin A activity. Epidemiological studies suggest protective effects of lycopene on some types of cancer, e.g., prostate cancer. In vitro and in vivo studies on growth of tumor cells support this conclusion. The major sources of lycopene for the human are tomatoes and tomato products, and bioavailability from different food items varies considerably. Lycopene oxidation products have recently been identified in human serum. Suggested health effects of lycopene require further investigation.
Antioxidants↗
Analysis of connexin43 gene expression induced by retinoic acid in F9 teratocarcinoma cells.
All-trans retinoic acid (10(-7) M) induces cell-cell communication and expression of the gap junction protein connexin43 in mouse F9 teratocarcinoma cells. Northern blot analysis revealed an increase of connexin43 mRNA after treatment with retinoic acid, accompanied by an increase of the mRNA of collagen IV, a differentiation marker. To address the question at what level gene expression is enhanced by retinoic acid, nuclear run-on experiments were carried out. There was no detectable change in the level of newly transcribed connexin43 mRNA. Therefore, we postulate a post-transcriptional mechanism responsible for the regulation of connexin43 mRNA levels by retinoic acid.
Actins↗
DNA damage by peroxynitrite characterized with DNA repair enzymes.
The DNA damage induced by peroxynitrite in isolated bacteriophage PM2 DNA was characterized by means of several repair enzymes with defined substrate specificities. Similar results were obtained with peroxynitrite itself and with 3-morpholinosydnonimine (SIN-1), a compound generating the precursors of peroxynitrite, nitric oxide and superoxide. A high number of base modifications sensitive to Fpg protein which, according to HPLC analysis, were mostly 8-hydroxyguanine residues, and half as many single-strand breaks were observed, while the numbers of oxidized pyrimidines (sensitive to endonuclease III) and of sites of base loss (sensitive to exonuclease III or T4 endonuclease V) were relatively low. This DNA damage profile caused by peroxynitrite is significantly different from that obtained with hydroxyl radicals or with singlet molecular oxygen. The effects of various radical scavengers and other additives (t-butanol, selenomethionine, selenocystine, desferrioxamine) were the same for single-strand breaks and Fpg-sensitive modifications and indicate that a single reactive intermediate but not peroxynitrite itself is responsible for the damage.
Butanols↗
Attenuation of oxidation and nitration reactions of peroxynitrite by selenomethionine, selenocystine and ebselen.
The effect of the selenium-containing compounds selenomethionine, selenocystine and ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one] on the oxidation of dihydrorhodamine 123 caused by peroxynitrite and on the nitration of 4-hydroxyphenylacetate by peroxynitrite was studied in comparison with their sulphur analogues methionine, cystine and ebsulfur [2-phenyl-1,2-benzisothiazol-3(2H)-one]. The selenocompounds protected dihydrorhodamine 123 from oxidation and 4-hydroxyphenylacetate from nitration more effectively than their sulphur analogues. Sodium selenite exhibited no effect. These observations are corollaries to the recent finding [Roussyn, Briviba, Masumoto and Sies (1996) Arch. Biochem. Biophys. 330, 216-218] that selenium-containing compounds are efficient in protecting against peroxynitrite-induced DNA single-strand breaks.
Azoles↗