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PubMed2004

DNA modification by oxovanadium(IV) complexes of salen derivatives.

Oxovanadium(IV) complexes of hydroxysalen derivatives have been prepared and tested as DNA reactive agents. The nuclease activity has been investigated under oxidative or reducing conditions, on the basis of the various oxidation states of vanadium: V(III), V(IV) and V(V). In the absence of an activating agent, none of the compounds tested was able to induce cleavage of DNA, whereas in the presence of mercaptopropionic acid (MPA) or Oxone the four complexes induced DNA modifications. Under both conditions, the para-hydroxy complex was found to be the most active compound. Reaction of these salen complexes with DNA occurs essentially at guanine residues and is more efficient in the presence of Oxone than under reducing conditions. The extent of Oxone-mediated DNA oxidation by the four vanadyl complexes was clearly superior to VOSO(4) and was observed without piperidine treatment. EPR studies provided information on the reactive metal-oxo species involved under each conditions and a mechanism of reaction with DNA is discussed.

DNA, Superhelical↗

PubMed1990

Extent of helix perturbation associated with DNA modification by the o-acetyl derivative of the carcinogen 4-hydroxyaminoquinoline-1-oxide.

Duplex unwinding associated with DNA modification by 4-acetoxyaminoquinoline-1-oxide, a model ultimate carcinogen of 4-nitroquinoline-1-oxide, has been determined by the agarose gel electrophoresis band-shift method. An average unwinding angle per stable adduct of -15.1 degrees +/- 1.5 degrees for negatively supercoiled topoisomers and -6.5 degrees +/- 1.4 degrees for positively supercoiled topoisomers was obtained. Because of the different proportion of stable adducts (dGuo-N2-AQO, dGuo-C8-AQO, dAdo-N6-AQO) between negatively (8:1.5:0.5) and positively (5:2.5:1) supercoiled topoisomers, the difference in unwinding angles is suggestive of a diverse contribution of the various adducts to the overall conformational change. Since the largest unwinding angle was coupled with the highest proportion of dGuo-N2-AQO adduct, it is likely that this adduct is the most distortive lesion. A contribution of sites of base loss to DNA unwinding was also observed.

Aminoquinolines↗

PubMed1989

32P-postlabeling assay for carcinogen-DNA adducts and other dna modifications.

32P-postlabeling analysis is a recently developed, highly sensitive method for the detection and measurement of covalent DNA adducts. Since the method does not require radioactive carcinogens, it is suitable for DNA of humans exposed to environmental or occupational genotoxicants. The basic procedure entails the enzymatic incorporation of 32P-label into enzymatic digestion products of DNA, the chromatographic separation and autoradiographic detection of the 32P-labeled digestion products and their quantitation by scintillation counting. Since only microgram amounts of DNA are required, the assay is well suited for the analysis of DNA lesions whenever only limited amounts of cells or tissue may be available. Various versions of the assay have been described affording different sensitivities of adduct detection. Under optimal conditions, one aromatic or bulky/hydrophobic adduct in 10(8) - 10(10) nucleotides can be detected and measured (this corresponds to 0.0003 - 0.03 fmol adduct/microgram DNA or 0.1 - 10 nmol adduct/mol DNA-P). The assay has been successfully applied to a variety of mutagenic (genotoxic) as well as non-mutagenic carcinogens. Among the latter are estrogens and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In addition, the assay detects age-dependent DNA modifications (I-compounds) in animals that have not been knowingly exposed to mutagens/carcinogens. In humans, the 32P-postlabeling assay has been applied to cigarette smokers, iron foundry workers and coke oven workers. Estimation of total aromatic adduct levels in exposed individuals gave values of 1 adduct in 10(6) - 10(8) DNA nucleotides. These values are similar to the total levels of persistent adducts in tissues of animals after exposure to initiating or carcinogenic doses of authentic aromatic geno-toxicants.

Aging↗

PubMed1992

Photochemical DNA modifications induced by 1,2-dioxetanes.

1,2-Dioxetanes are efficient sources of triplet excited carbonyl compounds, into which they decompose on thermal or photochemical activation. In the presence of DNA, the decomposition of dioxetanes gives rise to DNA modifications, which have been studied by means of specific repair endonucleases. Cyclobutane pyrimidine dimers, which are generated by triplet-triplet energy transfer, were detected by a UV endonuclease; they made up between 2% and 30% of the total modifications recognized by a crude repair endonuclease preparation from Micrococcus luteus. For various 1,2-dioxetanes, the yield of pyrimidine dimers was proportional to their triplet excitation flux. DNA strand breaks, sites of base loss (AP sites; recognized by exonuclease III and endonuclease IV) and dihydropyrimidines (recognized by endonuclease III) were found to represent only a small fraction of the modifications. The majority of the modifications detected were recognized by formamidopyrimidine-DNA glycosylase (FPG protein) and represent 8-hydroxyguanine (7,8-dihydro-8-oxoguanine) residues or other yet not defined base modifications which are recognized by this enzyme. The modifications were generated in similar relative yields by thermal and photo-induced decomposition of the 1,2-dioxetanes and therefore emanate under both conditions from the excited carbonyl compounds. The formation of the FPG protein-sensitive modifications was efficiently quenched by azide anions; the Stern-Volmer quenching of these modifications was 150-fold more effective than that of the pyrimidine dimers. The relative amounts of the two types of modifications were strongly dependent on the structure of the 1,2-dioxetanes and on the concentration of molecular oxygen. Singlet oxygen appears to be involved only to some extent in the generation of the FPG protein-sensitive base modifications as their yield was only moderately (approximately 2-fold) increased in D2O as solvent. A mechanism is suggested in which oxidized guanine is predominantly formed by a single-electron-transfer reaction of the triplet excited carbonyl product derived from the 1,2-dioxetane, followed by unknown secondary oxidations, which involve molecular oxygen and/or undecomposed 1,2-dioxetane.

DNA↗

PubMed1992

The formation and enzymatic repair of DNA modifications caused by the haloethylnitrosoureas and related compounds.

The haloethylnitrosoureas are both useful antitumor agents and known carcinogens. These biological activities are believed to be associated with DNA modification, and some biologically significant lesions have been identified in DNA exposed to these agents. At the same time, DNA repair is a cause of resistance to treatment by these agents, and may also serve as protection against their carcinogenic effects.

Animals↗

PubMed1990

Induction of covalent DNA modifications and micronucleated erythrocytes by 4-nitroquinoline 1-oxide in adult and fetal mice.

Pregnancy and development are known to modify carcinogenesis. Little is known about the mechanism for the modulation. These studies investigated the relative sensitivity of nonpregnant, pregnant, and fetal mice to the induction of covalent DNA modifications and micronucleated erythrocytes by 4-nitroquinoline 1-oxide (4-NQO). Our results revealed that 4-NQO was bound to guanine nucleotides of DNA in all maternal and fetal organs tested. The adduct levels ranged from 2-60 base modifications per 10(9) DNA bases when 4-NQO was administered s.c. Overall, 4-NQO bound preferentially to DNA of the maternal tissues compared with that of the corresponding fetal tissues, with the exception of the liver. The adduct levels in maternal and fetal organs fell into 3 distinct levels. The greatest binding was in maternal lungs and pancreas (the target organs for carcinogenesis). The lowest binding levels were in maternal liver and all fetal organs studied. Gestation age at the time of 4-NQO treatment did not produce a significant effect on the amounts of adduct formation in the tissues examined, with the exception of placenta and bone marrow. Chronic treatment did not affect binding preference. At the cellular level, 4-NQO treatment induced twice the frequency of micronucleated erythrocytes in the bone marrow of pregnant mice compared with the nonpregnant mice and fetal liver, on a mg/kg basis. However, the polychromatic erythrocytes of fetal liver were more sensitive than those of adult bone marrow to the induction of micronuclei, when adduct levels were taken into account. A positive correlation of organotropsim between 4-NQO-induced DNA adducts and carcinogenicity was observed for maternal tissues, but not for fetal tissues. Fetal tissues, overall, lack the enzymes to metabolically activate 4-NQO. Fetal cells elicit greater biological responses, compared with adult cells, at equal adduct levels. This study reveals that the effective doses in maternal and fetal tissues may differ and, therefore, will be a better basis for further understanding the molecular mechanism of transplacental carcinogenesis.

4-Nitroquinoline-1-oxide↗

PubMed1986

Nature and biological significance of DNA modification by the haloethylnitrosoureas.

The haloethylnitrosoureas are both successful antitumour agents and laboratory carcinogens. A growing body of evidence suggests that their biological activities result from DNA modification. By decomposing in different ways, the haloethylnitrosoureas generate intermediates that can introduce either hydroxyethyl or haloethyl groups into DNA. One hydroxyethyl derivative, O6-hydroxyethylguanine, may be responsible for at least some of the carcinogenicity of these compounds. Haloethyl derivatives lead to cross-linked structures which may be cytotoxic. Two such cross-links, 1-(3-deoxycytidyl)-2-(1-deoxyguanosinyl)ethane (dCydCH2CH2dGuo) and 1,2-bis(7-guanyl)ethane (GuaCH2CH2Gua), have been isolated from DNA that has been reacted with haloethylnitrosoureas. Various DNA repair mechanisms, including O6-alkylguanine-DNA alkyltransferase, evidently play a role in modulating both the carcinogenic and cytotoxic actions of these agents.

Antineoplastic Agents↗

PubMed1985

DNA modification by chemical carcinogens.

The chemistry and molecular biology of DNA adducts is only one part of the carcinogenic process. Many other factors will determine whether a particular chemical will exert a carcinogenic effect. For example, the size of particles upon which a carcinogenic may be adsorbed will influence whether or not, and if so where, deposition within the lung will occur. The simultaneous exposure to several different agents may enhance or inhibit the metabolism of a chemical to its ultimate carcinogenic form (Rice et al., 1984; Smolarek and Baird, 1984). The ultimate carcinogenic metabolites may be influenced in their ability to react with DNA by a number of factors such as internal levels of detoxifying enzymes, the presence of other metabolic intermediates such as glutathione with which they could react either enzymatically or non-enzymatically, and the state of DNA which is probably most heavily influenced by whether or not the cell is undergoing replication or particular sequences being expressed. Replicating forks have been shown to be more extensively modified than other areas of DNA. Another critical factor which can influence the final outcome of the DNA damage is whether or not the modifications can be repaired. If this occurs with high fidelity and the cell has not previously undergone replication then the effect of the damage by the carcinogen is likely to be minimal. The major area in which progress is needed is an understanding of what this damage really does to the cell such that after an additional period of time, which may be as long as twenty or more years, these prior events are expressed and cell proliferation occurs. Clearly additional stimulatory factors, for example tumor promoting agents such as the phorbol esters or phenobarbital, are often needed. After such prolonged periods it seems likely that the DNA adducts would no longer be present. However, the way in which their earlier presence is remembered is not clear. Simple mutations do not explain all the characteristics of tumor progression and, when it occurs, regression. Even if a specific site mutation does occur then its expression must be under other types of control. Any explanation of the action of DNA modification at the molecular level also requires that account be taken of the diverse nature of the DNA adducts from simple modifications such as methylation to bulkier adducts such as benzo[a]pyrene, aflatoxin or aromatic amines.(ABSTRACT TRUNCATED AT 400 WORDS)

4-Nitroquinoline-1-oxide↗

PubMed1992

Modulation of DNA modification (I-compound) levels in rat liver and kidney by dietary carbohydrate, protein, fat, vitamin, and mineral content.

I-compounds are DNA modifications detected by 32P-postlabeling that increase with age in rodents without known carcinogen exposure. Diet type (natural ingredient versus purified) greatly influences patterns and levels of I-compounds. To test the hypothesis that I-compound formation is affected, also, by dietary macro- and micronutrients, effects of carbohydrate, protein, fat, vitamin, and mineral content on rat liver and kidney I-compounds were determined. Female Sprague-Dawley rats were fed basic or modified AIN-76A purified diets for 3-6 months. High protein (HP) diet (50%, w/w) increased I-compound levels in liver but not kidney. High carbohydrate (HC) diet (78%) produced a significant increase in the polar as well as total I-compound levels in both tissues. High fat diets (20%) elicited significantly lower levels of liver I-compounds than HC, HP, and basic diets. There were few significant differences between high polyunsaturated (safflower oil) and saturated fat (lard) diet groups. No qualitative differences in I-compound profiles were observed in either tissue. In rats fed basic diet supplemented with vitamins and/or minerals, increased vitamin content reduced the levels of polar I-compounds in liver. No extra diet-induced adducts were observed; all effects were of a quantitative nature. These data provide direct evidence that nutrients significantly influence I-compound levels and support the hypothesis that normal metabolism of nutrients leads to the production of small amounts of DNA-reactive electrophiles. These observations suggest a novel mechanism where nutrient composition of the diet may play a role in development of neoplasia and other adverse health effects.

Aging↗

PubMed1998

DNA modifications by the mutagen glyoxal: adduction to G and C, deamination of C and GC and GA cross-linking.

The mutagen glyoxal was reacted with DNA or deoxynucleosides under physiological conditions (pH 7.4, 37 degrees C) in vitro and the products were analyzed by HPLC coupled with a photodiode array UV detector. The efficient formation of a cyclic glyoxal-dG adduct (dG+) was observed in DNA, as well as with dG. The monomeric dG + was gradually decomposed to dG at pH 7.4 and 37 degrees C (t1/2 14.8 h). However, the dG+ formed in single- and double-stranded DNA was rather stable under physiological conditions and the half-lives were 19 and 40 times longer respectively than that of the monomer (t1/2 285 and 595 h respectively). By reaction of glyoxal with deoxycytidine (dC), the deamination products deoxyuridine and 5-hydroxyacetyl-dC (dC+) were formed. Under the same conditions, 5-methyl-dC was deaminated to dT at a higher rate. Deoxyuridine was also formed in DNA by glyoxal treatment. When glyoxal was reacted with various combinations of deoxynucleosides for a prolonged period, dG-glyoxal-dC (GgC), dG-glyoxal-dA (GgA), dG-glyoxal-dG (GgG) and dC-glyoxal-dC (CgC) cross-links were detected, although structures were not assigned unequivocally. Among these, the former two, the GC and GA cross-links, were detected in glyoxal-treated DNA. The yields of these products in DNA were in the following order; dG+ > dU > GgA > GgC > dC+. These DNA modifications may be relevant to glyoxal-induced mutations at GC pairs.

Cytosine↗

PubMed1990

Modulation of benzo[a]pyrene-induced covalent DNA modifications in adult and fetal mouse tissues by gestation stage.

In these studies, we investigated the influence of gestation age on the induction of covalent DNA modifications by benzo[a]pyrene (B[a]P). Timed-pregnant ICR mice were given a single treatment of B[a]P (80 mg/kg, p.o.) on different days of gestation, killed 24 h later and analyzed for the presence of B[a]P-induced DNA adducts using the P1 nuclease version of the 32P-postlabeling method. Our results showed that B[a]P bound to embryonic, placental, fetal and maternal DNA throughout gestation with gestation-stage dependency. Overall, B[a]P bound less to maternal DNA during organogenesis and placentation compared to other stages of gestation and to the non-pregnant stage. The ontogenesis of B[a]P-induced DNA adducts in fetal tissues exhibited organ specificity that had two different types of profiles. With advancing gestation age, one type (lung, carcass and placenta) exhibited a steady linear increase, and the other type [gastrointestinal tract (GIT) and skin] a biphasic increase. In the fetal and maternal organs, adduct levels peaked 2 days before parturition. Over the course of gestation, fetal adduct levels were 70-100% of adult levels in the skin, 7-12% in the GIT, 25-40% in the liver and 15-80% in the lung. The adduct levels in many fetal organs exhibited little relationship to placental adduct levels throughout gestation. Collectively, our results indicate that: (i) transplacental DNA damage induced by B[a]P is determined mainly by fetal competence in metabolic activation and/or detoxification of B[a]P; and (ii) events occurring during placentation and organogenesis inhibit B[a]P binding to maternal tissues.

Animals↗

PubMed1989

Influence of the degree of DNA modification on the immunochemical determination of cisplatin-DNA adduct levels.

Two different enzyme-linked immunosorbent assays (ELISAs) are used for the sensitive determination of cisplatin-DNA adducts in, for example, blood cells of cisplatin-treated cancer patients. Poirier et al. determined the adducts in native DNA with an antiserum raised against highly modified cisplatin-DNA. Fichtinger-Schepman et al. assayed the various adducts after chromatography of enzymatically digested DNA samples, with antibodies raised against synthetic haptens mimicking the Pt-containing digestion products. In identical human samples analysed by both methods, 14- to 300-fold higher adduct levels were found with the Fichtinger-Schepman method. Adduct levels in organ samples of cisplatin-treated rats and mice allowed comparison of both ELISAs with independent Pt assays (atomic absorption spectroscopy, AAS). AAS data confirmed the results of the Fichtinger-Schepman assay, whereas ELISAs according to Poirier showed differences up to a factor of 1000. Analysis of cisplatin adducts in in vitro modified DNA revealed that the Poirier antibodies yield correct estimates with highly modified DNA, but fall short at low platination levels: no adducts could be detected in samples modified to a level similar to that found in blood cells from cisplatin-treated patients. The positive responses obtained with samples of such patients, who had been treated repeatedly, might be explained if cisplatin adducts are preferentially formed around persistent lesions from the previous treatments.

Animals↗

PubMed2003

Immunochemical study of DNA modifications in the nuclei of UV-damaged lymphocytes.

Studies of UV-induced skin cancers show that malignisation of skin cells, as well as alterations in anti-tumor immune control, are triggered by UV-induced lesions in cellular DNA. Such lesions can probably appear in the human mononuclear leukocytes (lymphocytes) during exposure of skin to sunlight. With the aim of studying the processing of UV-induced DNA lesions in these cells, we used flow cytometry and labelling of their partially denatured nuclei with the monoclonal antibody (H3) that binds cyclobutane pyrimidine dimers in single-stranded DNA. After the first few hours of cultivation of the irradiated cells, we found an increase in H3-specific fluorescence from cellular nuclei, while there was a decrease in the number of H3-positive sites in isolated DNA from these cells. We examined cells cultured under different conditions and concluded that the effect of enhancement of H3 labelling of nuclei did not result from changes in temperature and culture medium. Furthermore, we have found that this effect, as well as the decrease in H3 labelling in isolated DNA, are both prevented by pretreatment of the cells with Novobiocin, which we used as an inhibitor for the topoisomerase II-induced relaxation of supercoiled DNA prior to repair-specific incision. The inhibition by Novobiocin of the above-mentioned changes in H3 labelling in cellular nuclei and isolated DNA of the irradiated cells clearly indicate the association of both effects with an excision repair-related DNA modification. While the partial loss of H3-binding sites from isolated DNA is obviously a result of excision of some fraction of pyrimidine dimers, the enhancement of the H3 labelling of nuclei might be due to the formation of open structures at dipyrimidine-containing DNA fragments in preparation for incision. We suggest that formation of open structures predominates quantitatively over dual incision and excision of these fragments, and leads to enhanced exposure of the pyrimidine dimers in nuclei to H3 binding. Thus, unstimulated human lymphocytes appear to be capable of performing pre-incision steps for removal of these DNA lesions.

Cell Nucleus↗

PubMed1994

Investigation of ionizable residues critical for sequence-specific enzymatic DNA modification: protein modification and steady-state and pre-steady-state kinetic pH analyses of EcoRI DNA methyltransferase.

Steady-and pre-steady-state pH kinetic analyses are widely used methods to investigate important ionizable groups in enzyme-catalyzed reactions. The first such analysis to identify ionizable residues critical for sequence-specific modification of DNA is presented. EcoRI DNA methyltransferase uses S-adenosyl-L-methionine (AdoMet) to catalyze the N6 methylation of the second adenine in the double-stranded DNA sequence GAATTC. The kinetic mechanism was previously shown to be steady-state-ordered bi bi in which AdoMet binds first followed by DNA addition [Reich, N. O., & Mashhoon, N. (1991) Biochemistry 30, 2933-2939]. Steady-state parameters are strongly dependent on pH and implicate at least four residues with pKa values between 8.2 and 8.9 in the free enzyme and AdoMet-Bound enzyme and one residue with an apparent pKa of 6.0. The data obtained are consistent with the enzyme binding the form of AdoMet in which the alpha amino group is protonated. Two protein residues with an apparent pKa between 8.9 and 9.2 were implicated within the central complex (enzyme-DNA-AdoMet). The general insensitivity of all steady-state parameters to pH changes between pH 6.0 and 8.0 suggests that no critical protein residues undergo ionization-state changes in this range. The lack of significant pH-dependent changes in protein fluorescence and DNA thermal stability suggests minimal structural changes in either macromolecule. In support of the steady-state results single-turnover experiments reveal minimal pH dependence of the methylation rate constant between pH 5.53 and 8.6. Thus, no amino acids critical for catalysis undergo ionization-state changes in this range.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗

PubMed1989

The detection of extremely rare DNA modifications. Methylation in dam- and hsd- Escherichia coli strains.

DNA methylation in Escherichia coli plays a role in many key cellular processes, including DNA replication, repair, restriction, and transcription. However, several mutant bacterial strains exist which are deficient in DNA methylase activities. Thus, it has been suggested that methylation produced by the dam (DNA adenine methylase) gene is required for the viability of E. coli and that dam- strains still produce low levels of methylation. Current experimental methods are not sensitive enough to detect a few potentially essential methylated sites per genome. Here we describe a method for the detection of N6-methyladenine at specific sites with a sensitivity of one site in more than 10 megabases. We show that methylation produced by both the dam and hsd (EcoK) genes is not required for the growth of E. coli and identify the site of EcoK modification. Minor adaptations of the technique should enable the identification of other rare DNA modifications.

Base Sequence↗

PubMed1980

Mutagenicity of carcinogenic methylating agents is associated with a specific DNA modification.

The carcinogenic potency of simple aliphatic alkylating agents such as the alkylnitrosamides and the alkylmethanesulphonates is positively correlated with their ability to alkylate the relatively weakly nucleophilic oxygen atoms in DNA, particularly the O6-atom of guanine. Differences in the spectrum of DNA alkylations produced by these agents can be rationalised on chemical grounds in that the electrophilic reactivity of the alkylating species determines the extent to which it will react at sites of weaker nucleophilicity. Alkylation of the more strongly nucleophilic ring nitrogen atoms of the purine bases, which is the main site of reaction with all these agents, appears to be much less important in alkylation carcinogenesis. O6-alkylation of guanine is likely to interfere with DNA base-pair hydrogen bonding and is possibly the major DNA modification responsible for the induction of GC yields AT transition mutations in bacteria and bacteriophage by alkylating agents. Here, we have studied the effects of three methylating agents of contrasting carcinogenic potency on mammalian (V79 Chinese hamster) cells in in culture. We report that the mutagenicity but not the cytotoxicity of each agent reflects its carcinogenicity and, furthermore, that the marked differences in mutagenicity are closely paralleled by differences in levels of O6-guanine methylation.

Alkylating Agents↗

PubMed2001

Phenotypes of Drosophila homologs of human XPF and XPG to chemically-induced DNA modifications.

DmXPF (mei9) and DmXPG (mus201) mutants are Drosophila homologs of the mammalian XPF and XPG genes, respectively. For Drosophila germ cells, causal correlations exist between the magnitude of a potentiating effect of a deficiency in these functions, measured as the M(NER-)/M(NER+) mutability ratio, and the type of DNA modification. M(NER-)/M(NER+) mutability ratios may vary with time interval between DNA adduct formation and repair, mutagen dose and depend also on the genetic endpoint measured. For forward mutations, there is no indication of any differential response of DmXPF compared to DmXPG. Subtle features appeared from a class-by-class comparison: (i) Methylating agents always produce higher M(NER-)/M(NER+) ratios than their ethylating analogs; (ii) M(NER-)/M(NER+) mutability ratios are significantly enhanced for cross-linking N-mustards, aziridine and di-epoxide compounds, but not for cross-linking nitrosoureas. The low hypermutability effects with bifunctional nitrogen mustards, aziridine and epoxide compounds are attributed to unrepaired mono-alkyl adducts; (iii) The efficient repair of mono-alkyl-adducts at ring nitrogens in wild-type germ cells is evident from the absence of a dose-response relationship for ethylene oxide, propylene imine and methyl methanesulfonate (MMS). These chemicals become powerful germline mutagens when the NER system is disrupted. Systematic studies of the type performed on germ cells are not available for somatic cells of Drosophila. The sparse data available show large differences in the response of germ cells and somatic cells. The bifunctional agent mechlorethamine (MEC) but not the monofunctional MMS or 2-chloroethylamine cause in NER(-) XXfemale symbol the highest potentiating effect on mitotic recombination. The causes of the discrepancy between the extraordinarily high activity of MEC in mus201 somatic cells and its low potentiating effect in germ cells is unknown at present.

Animals↗

PubMed1996

Extreme exercise and oxidative DNA modification.

Extreme exercise increases oxygen uptake with a potential for increased formation of reactive oxygen species. Damage to biomolecules may occur if such an increase exceeds the protective capacity of antioxidant defence mechanisms. Vigorous exercise amounting to approximately 10 h a day for 30 days increased the rate of oxidative DNA modification by 33% (95% confidence limits, 3-67%; P < 0.02) in 20 men owing to the urinary excretion of 8-oxo-7,8-dihydro-2'-deoxyguanosine, an oxidatively modified deoxynucleoside originating from nuclear DNA repair, oxidation of the nucleotide pool from mitochondrial DNA and/or from cell turnover. Oxidative stress to DNA points to a risk for the development of cancer and premature ageing from extreme exercise.

8-Hydroxy-2'-Deoxyguanosine↗