Genotoxic flavonoids and red wine: a possible role in stomach carcinogenesis.
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Carcinogens↗
Biomedical subjects
J Rueff
Publications and source records attributed to J Rueff.
DNA strand breaks and chromosomal aberrations induced by H2O2 and 60Co gamma-radiation.
DNA strand breaks and chromosomal aberrations (CAs) were studied in human cells treated with hydrogen peroxide or with ionizing radiation. DNA strand breaks could be produced at dose levels of H2O2 much lower than those which induced CAs. Doses as low as 0.5 mM of H2O2 produced about as many DNA strand breaks as 2 Gy of 60Co gamma-radiation. On the other hand, as much as 20 mM H2O2 produced only half as many CAs as 1 Gy of 60Co gamma-radiation. The different mechanisms involved in the production of human genetic damage by H2O2 and gamma-radiation are discussed.
Adult↗
Genotoxicity of nitrosated red wine and of the nitrosatable phenolic compounds present in wine: tyramine, quercetin and malvidine-3-glucoside.
Phenolic compounds and biogenic amines are known to be present in some foodstuffs which become directly genotoxic after nitrosation in vitro. Red wine has previously been shown to be genotoxic and this activity has been attributed mainly to flavonoids. Besides flavonoids, red wine contains a multiplicity of compounds, including biogenic amines. Using the Ames assay and the SOS chromotest, this study has shown that red wine and some of the nitrosatable molecules present in wine become directly genotoxic on nitrosation in vitro: these include the phenolic molecules tyramine, quercetin and malvidine-3-glucoside, whereas phenylethylamine and histamine were negative on nitrosation. Interestingly, quercetin had been predicted to be negative after nitrosation, using the CASE methodology. The concentrations of these three positive nitrosatable compounds in wine were determined by HPLC. Comparison of these concentrations and their respective levels of genotoxicity suggests that the genotoxicity after nitrosation is probably attributable to other molecules. It is also possible that synergistic effects may occur between various nitrosatable compounds in wine.
Anthocyanins↗
Quercetin and the mutagenicity of wines.
Various studies have shown the mutagenicity of red wine. The major mutagens identified in red wine have been flavonoids, i.e. rutin and its aglycone quercetin. Besides flavonoids, however, it has recently been reported that H2O2 may account for the mutagenicity of red wine in the L-Arabinose resistance test. In the present study we report on the role of flavonoids in the mutagenicity of red wine in the Ames assay. Different wines from Portugal and Spain have been tested after concentration in XAD-2 columns in strains TA98 and TA104 of Salmonella typhimurium concurrently with the determination of the respective content of quercetin by HPLC. A similar approach was used for pilot scale productions of red wines. In all cases quercetin could be demonstrated as the major mutagen in red wines. The levels of quercetin in finished wines and during the wine-making process showed a good fit with the levels of mutagenicity detected. Catalase had no effect whatsoever on the mutagenicity of wines in both TA98 and TA104. These results do not rule out a role for H2O2 in the mutagenicity of wines, detected in other genetic end-points, because H2O2 can be formed from the auto-oxidation of quercetin.
Animals↗
Oxygen species and the genotoxicity of quercetin.
Quercetin has been extensively studied in various short-term assays for genotoxicity. The patterns of genotoxicity of quercetin for different genetic endpoints are subject to a variety of factors (pH, antioxidants, metabolism) whose precise role in each test remains unclear. In the present study we report on the possible effect of oxygen-derived species on the activity of quercetin in the Ames assay and in the SOS chromotest. Our results seem to suggest that superoxide dismutase (SOD) does not account for the levels of mutagenicity detected in the presence of S9 or S100. The latter may, however, contain other factors of antioxidant defense which may prevent the oxidative degradation of quercetin. Since this degradation occurs at pH values above neutrality and the SOS-inducing activity is higher at pH 6.0, it is concluded that the response of quercetin in the SOS chromotest is due to quercetin itself at acidic pH. The SOS-inducing activity at pH 7.4 is enhanced by SOD, but it cannot be unambiguously concluded that this effect in the SOS chromotest might only be due to protection against the oxidative degradation of quercetin.
Animals↗
Activation of promutagens by porphyrinic biomimetic systems.
Biomimetic oxidative systems using tetraarylporphyrins, which can bind various metals, and exogenous oxygen donors have been extensively studied as models of the natural heme prosthetic group. Those systems were shown to catalyze oxidations in a manner consistent with cytochromes P-450 and usefully contributed to an understanding of the mechanisms of the cytochromes P-450-dependent reactions when using oxygen donors. The usage of those systems in mutagenicity studies showed that some promutagens could be activated to proximate mutagens. In the present work we report on the activation of benzo[a]pyrene, 3-methylcholanthrene, 7,12-dimethylbenz[a]anthracene; 2-aminofluorene, 2-acetylaminofluorene and the heterocyclic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) to Ames assay mutagens using tetraphenylporphinatoiron(III) chloride and various oxygen donors, namely iodosylbenzene, cumene hydroperoxide, tert-butylhydroperoxide and H2O2. Our results demonstrate that IQ could be activated using any of the oxygen donors. However, a pattern of specificity for the oxygen donor could be identified. Polycyclic aromatic hydrocarbons displayed higher levels of mutagenicity with iodosylbenzene, whereas aromatic amines were preferentially activated when tert-butylhydroperoxide was used. For the heterocyclic amine IQ the higher responses were obtained using cumene hydroperoxide. The putative non-carcinogen pyrene and the controversial carcinogen quercetin were not activated irrespective of the oxygen donor used.
Dose-Response Relationship, Drug↗
Mutagenic activity in the wine-making process: correlations with rutin and quercetin levels.
Mutagenic activity was monitored during the time course of the vinification process of a Portuguese red wine using the Ames assay. Dependence upon faecalase treatment for detection of mutagenicity was evaluated concurrently with HPLC analysis of the flavonoids rutin and quercetin. Rutin (quercetin-o-3-rutinoside) is liberated from the grapes during the first 10 days of the process and is hydrolysed as the vinification process proceeds. This explains the levels of the free quercetin in the wine and mutagenicity in the absence of faecalase treatment. Mutagenicity in the presence of faecalase during the first 26 days of the process correlates with the levels of rutin, and in the absence of faecalase the highest mutagenic activity detected (160th day) coincides with the highest level of free quercetin. Our results do not rule out the possibility that other mutagens are present in wines, in particular oxidative-type mutagens.
Animals↗
The frequency and origin of the sickle cell mutation in the district of Coruche/Portugal.
The frequency of the beta S mutation in the district of Coruche/Portugal is estimated to be about 4% from analysis of a group of 181 school children and their teachers in an area in which malaria has been endemic until recently. Several white Portuguese patients with sickle cell disease (six homozygous SS and one S beta degree thalassaemia) were found in a group of 309 further patients who were known and followed up by local medical practitioners. These patients had clinical and haematological features similar to patients of African origin, although their growth and sexual development appeared to be normal. The analysis of an array of polymorphic restriction sites within the beta S globin gene cluster (beta S haplotype) showed patterns that are known to occur in Africa. The frequencies of the three main African beta S haplotypes termed Senegal, Bantu, and Benin reflect the extent of Portuguese naval explorations. It is concluded that the sickle cell gene in Portugal has probably been imported from Africa and has been amplified in comparison with other genes characteristic for African races because of the selective advantage of AS heterozygotes in an area endemic for malaria.
Adolescent↗
Mutagenicity of rutin and the glycosidic activity of cultured cell-free microbial preparations of human faeces and saliva.
Genotoxic testing of flavonol glycosides, which account for most of the human intake of flavonoids, is dependent on the use of enzymatic extracts that exhibit beta-glycosidic activity. This study was aimed at characterizing further the beta-glycosidic activity of cultured cell-free microbial extracts from human faeces (faecalase) and saliva (salivase). Using o-nitrophenyl-beta-D-galactoside as substrate, the optimum pH and apparent Km and energy of activation were shown to be 7.6, 3.5 x 10(-4) M and 8.65 kcal/mol, respectively, for faecalase, and 7.4, 8.7 x 10(-5) M and 3.8 kcal/mol, respectively, for salivase. Rutin (quercetin-3-O-rutinoside) was shown to be a competitive inhibitor for faecalase, whereas no inhibitory activity could be found for salivase. Enzymatic hydrolysis of rutin gave the mutagenic product quercetin that was detected in the Ames assay and using high-performance liquid chromatography.
Cell-Free System↗
Oxidative stress in trisomy 21. A possible role in cataractogenesis.
Previous studies have suggested that free radicals and related species play a role in lens damage. The molecules involved may include proteins, lipids and DNA. Focal cortical changes and cortical liquefaction have been reported in patients with Down's syndrome over the age of 15 years. There is evidence supporting the hypothesis that trisomy 21 patients have an increase in free radical reactions and lipoperoxidation susceptibility. This could be due to an increase in the H2O2 generation catalysed by CuZn SOD although the activity of other gene products coded for on chromosome 21 cannot be excluded. Thiobarbituric acid reactive products were measured in human erythrocytes of nine DS patients and nine age-matched controls. There was a significant increase in the first group (21.0 +/- 2.3 nmol MDA/g Hb vs 16.4 +/- 2.9 nmol MDA/g Hb; p less than or equal to 0.01). In plasma, however, TBA products and antioxidant levels (ascorbic acid, tocopherol and uric acid) were not significantly different. Further studies should be carried out, namely through the use of more specific and sensitive methods, to assess the possible association between oxidative stress and cortical lens damage in DS patients.
Adolescent↗
Influence of S9 mix in the induction of SOS system by quercetin.
The induction of recA, umuC and sfiA genes by quercetin was studied in the presence and in the absence of S9 mix. The inducing activity of quercetin is higher for sfiA than for recA and umuC genes in the absence of S9 mix. The putative genotoxic metabolites of quercetin produced by S9 mix display different inducing activities of the three SOS genes as compared to quercetin. The induction of sfiA gene is decreased by the presence of S9 mix, whereas an opposite effect was observed concerning umuC and recA. These data suggest that the error-prone repair pathway participates in mutagenesis by quercetin and its metabolites. Moreover, the type of DNA damage exerted by quercetin seems to be determined by its metabolic fate. The importance of testing for the induction of other SOS genes, together with sfiA, in the study of SOS functions as a genotoxic index is emphasized.
Animals↗
Genetic toxicology of flavonoids: the role of metabolic conditions in the induction of reverse mutation, SOS functions and sister-chromatid exchanges.
Glycosides of flavonols such as quercetin, are found in the edible portions of most food vegetables. Flavonols present in plants as glycosides can be freed during fermentation. We have compared the DNA-damaging activity of quercetin, rutin (3-o-rutinoside of quercetin) and a fermented flavonoid-containing beverage, red wine, for different genetic end-points under different metabolic conditions. The genotoxicity of quercetin, rutin and commercial red wine has been studied for the induction of: (i) reverse mutation in the Ames assay; (ii) SOS functions in the SOS Chromotest; (iii) sister-chromatid exchanges (SCEs) in human lymphocytes. While in the Ames assay the mutagenicity of quercetin is enhanced by the presence of rat liver microsomal enzymes (S9) or the respective cytosolic fraction (S100), genotoxicity is reduced when the induction of SOS responses is assessed using the SOS Chromotest. Similarly, the induction of SCEs is lowered when testing in the presence of liver enzymes. Rutin has no activity whatsoever. Detection of activity of red wine in the three assays is not dependent upon hydrolysis by glycosidases and its content of quercetin accounts almost entirely for the levels of genotoxicity detected. The results suggest that the putative genotoxic metabolites of quercetin vary for different genetic end-points considered and that the metabolic fate of flavonoids might partly account for the conflicting data about their genotoxicity in vivo and carcinogenic activity.
Animals↗
Ten years' experience with trophoblastic tumors in Portugal.
Between 1971 and 1980, 220 patients were observed and treated. The patients were classified according to various parameters: age, previous pregnancies, pathology reports of specimens obtained from the uterus, and site of metastasis. The study stressed the possibility of 100% cure in patients with hydatidiform mole, while in choriocarcinoma, late diagnosis was responsible for the failure in effective treatment.
Adolescent↗
VLDL-associated mutagenic activity.
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Humans↗
Urinary mutagenicity in occupational exposure to mineral oils and iron oxide particles.
Mutagenicity in the urine of workers occupationally exposed to mineral oils and iron oxide particles and age matched workers only exposed to mineral oils was investigated using the Salmonella/mammalian microsome assay. Both groups of workers included smokers and non-smokers. Mutagenicity was significantly higher in the group of workers exposed to both mineral oils and iron oxide particles, the statistical significance of the difference being similar to that found when total non-smokers were compared with total smokers irrespective of occupational exposure. When only non-smokers of both groups of workers were compared, the extent of mutagenicity in the urine of workers exposed to iron oxide particles was still significantly higher, suggesting that smoking did not exhibit a significant enhancing effect on urinary mutagenicity of workers exposed to mineral oils and iron oxide particles, but instead seemed to enhance urinary mutagenicity similarly in both groups of workers. Whether or not this conclusion can be drawn may depend, among other factors, on the variability of the Ames assay. To cope with this particular problem, the possible usefulness of a mutagenicity factor is discussed.
Environmental Exposure↗
Mutagenicity in urine of workers in naval industry.
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Chromatography, Thin Layer↗