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At least 595 records · Page 33Linked to original sources
PubMed1998

The protein oxidation product 3,4-dihydroxyphenylalanine (DOPA) mediates oxidative DNA damage.

A major product of hydroxy-radical addition to tyrosine is 3, 4-dihydroxyphenylalanine (DOPA) which has reducing properties. Protein-bound DOPA (PB-DOPA) has been shown to be a major component of the stable reducing species formed during protein oxidation under several conditions. The aim of the present work was to investigate whether DOPA, and especially PB-DOPA, can mediate oxidative damage to DNA. We chose to generate PB-DOPA using mushroom tyrosinase, which catalyses the hydroxylation of tyrosine residues in protein. This permitted us to study the reactions of PB-DOPA in the virtual absence of other protein-bound oxidation products. The formation of two oxidation products of DNA, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8oxodG) and 5-hydroxy-2'-deoxycytidine (5OHdC), were studied with a novel HPLC using gradient elution and an electrochemical detection method, which allowed the detection of both DNA modifications in a single experiment. We found that exposure of calf thymus DNA to DOPA or PB-DOPA resulted in the formation of 8oxodG and 5OHdC, with the former predominating. The formation of these DNA oxidation products by either DOPA or PB-DOPA depended on the presence of oxygen, and also on the presence and on the concentration of transition metal ions, with copper being more effective than iron. The yields of 8oxodG and 5OHdC increased with DOPA concentration in proteins. Thus PB-DOPA was able to promote further radical-generating events, which then transferred damage to other biomolecules such as DNA.

Basidiomycota↗
PubMed2000

Potent inhibition of werner and bloom helicases by DNA minor groove binding drugs.

Maintenance of genomic integrity is vital to all organisms. A number of human genetic disorders, including Werner Syndrome, Bloom Syndrome and Rothmund-Thomson Syndrome, exhibit genomic instability with some phenotypic characteristics of premature aging and cancer predisposition. Presumably the aberrant cellular and clinical phenotypes in these disorders arise from defects in important DNA metabolic pathways such as replication, recombination or repair. These syndromes are all characterized by defects in a member of the RecQ family of DNA helicases. To obtain a better understanding of how these enzymes function in DNA metabolic pathways that directly influence chromosomal integrity, we have examined the effects of non-covalent DNA modifications on the catalytic activities of purified Werner (WRN) and Bloom (BLM) DNA helicases. A panel of DNA-binding ligands displaying unique properties for interacting with double helical DNA was tested for their effects on the unwinding activity of WRN and BLM helicases on a partial duplex DNA substrate. The levels of inhibition by a number of these compounds were distinct from previously reported values for viral, prokaryotic and eukaryotic helicases. The results demonstrate that BLM and WRN proteins exhibit similar sensitivity profiles to these DNA-binding ligands and are most potently inhibited by the structurally related minor groove binders distamycin A and netropsin (K(i) </=1 microM). The distinct inhibition of WRN and BLM helicases by the minor groove binders suggest that these helicases unwind double-stranded DNA by a related mechanism.

Adenosine Triphosphatases↗
PubMed2001

Hydroxyurea induces site-specific DNA damage via formation of hydrogen peroxide and nitric oxide.

Hydroxyurea is a chemotherapeutic agent used for the treatment of myeloproliferative disorders (MPD) and solid tumors. The mutagenic and carcinogenic potential of hydroxyurea has not been established, although hydroxyurea has been associated with an increased risk of leukemia in MPD patients. To clarify whether hydroxyurea has potential carcinogenicity, we examined site-specific DNA damage induced by hydroxyurea using (32)P-5'-end-labeled DNA fragments obtained from the human p53 and p16 tumor suppressor genes and the c-Ha-ras-1 protooncogene. Hydroxyurea caused Cu(II)-mediated DNA damage especially at thymine and cytosine residues. NADH efficiently enhanced hydroxyurea-induced DNA damage. The DNA damage was almost entirely inhibited by catalase and bathocuproine, a Cu(I)-specific chelator, suggesting the involvement of hydrogen peroxide (H(2)O(2)) and Cu(I). Typical free hydroxyl radical scavengers did not inhibit DNA damage by hydroxyurea, but methional did. These results suggest that crypto-hydroxyl radicals such as Cu(I)-hydroperoxo complex (Cu(I)-OOH) cause DNA damage. Formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) was induced by hydroxyurea in the presence of Cu(II). An electron spin resonance spectroscopic study using N-(dithiocarboxy)sarcosine as a nitric oxide (NO)-trapping reagent demonstrated that NO was generated from hydroxyurea in the presence and absence of catalase. In addition, the generation of formamide was detected by both gas chromatography-mass spectrometry (GC-MS) and time-of-flight-mass spectrometry (TOF-MS). A high concentration of hydroxyurea induced depurination at DNA bases in an H(2)O(2)-independent manner, and endonuclease IV treatment led to chain cleavages. These results suggest that hydroxyurea could induce base oxidation as the major pathway of DNA modification and depurination as a minor pathway. Therefore, it is considered that DNA damage by hydroxyurea participates in not only anti-cancer activity, but also carcinogenesis.

Animals↗
PubMed2006

Identification of a DNA restriction-modification system in Pectobacterium carotovorum strains isolated from Poland.

AIMS: Polish isolates of pectinolytic bacteria from the species Pectobacterium carotovorum were screened for the presence of a DNA restriction-modification (R-M) system. METHODS AND RESULTS: Eighty-nine strains of P. carotovorum were isolated from infected potato plants. Sixty-six strains belonged to P. carotovorum ssp. atrosepticum and 23 to P. carotovorum ssp. carotovorum. The presence of restriction enzyme Pca17AI, which is an isoschizomer of EcoRII endonuclease, was observed in all isolates of P. c. atrosepticum but not in P. c. carotovorum. The biochemical properties, PCR amplification, and sequences of the Pca17AI restriction endonuclease and methyltransferase genes were compared with the prototype EcoRII R-M system genes. Only when DNA isolated from cells of P. c. atrosepticum was used as a template, amplification of a 680 bp homologous to the gene coding EcoRII endonuclease. CONCLUSIONS: Endonuclease Pca17AI, having a relatively low temperature optimum, was identified. PCR amplification revealed that the nucleotide sequence of genes for EcoRII and Pca17AI R-M are different. Dcm methylation was observed in all strains of Pectobacterium and other Erwinia species tested. The sequence of a DNA fragment coding Dcm methylase in P. carotovorum was different from that of Escherichia coli. SIGNIFICANCE AND IMPACT OF THE STUDY: Pca17AI is the first psychrophilic isoschizomer of EcoRII endonuclease. The presence of specific Dcm methylation in chromosomal DNA isolated from P. carotovorum is described for the first time. A 680 bp PCR product, unique for P. c. atrosepticum strains, could serve as a molecular marker for detection of these bacteria in environmental samples.

Base Sequence↗
PubMed1991

Genotoxicity of singlet oxygen.

Singlet oxygen, 1O2 (1 delta g), fulfills essential prerequisites for a genotoxic substance, like hydroxyl radicals and other oxygen radicals: it can react efficiently with DNA and it can be generated inside cells, e.g. by photosensitization and enzymatic oxidation. As might be anticipated from the non-radical character of singlet oxygen, the pattern of DNA modifications it produces is very different from that caused by hydroxyl radicals. While hydroxyl radicals produce DNA strand breaks and sites of base loss (AP sites) in high yield and react with all four bases of DNA, singlet oxygen generates predominantly modified guanine residues and few strand breaks and AP sites. There is now convincing evidence that a major product of base modification caused by singlet oxygen is 8-hydroxyguanine (7,8-dihydro-8-oxoguanine). Indeed, the recently reported miscoding properties of 8-hydroxyguanine can explain the predominant type of mutations observed when DNA modified by singlet oxygen is replicated in cells. There are also strong indications that singlet oxygen generated by photosensitization can act as an ultimate DNA modifying species inside cells. However, indirect genotoxic mechanisms involving other reactive oxygen species produced from singlet oxygen are also possible and appear to predominate in some cases. The cellular defense system against oxidants consists of effective singlet oxygen scavengers such as carotenoids. The observation that carotenoids can inhibit neoplastic cell transformation when administered not only together with but also after the application of chemical or physical carcinogens might indicate a role of singlet oxygen in tumor promotion that could be independent of the direct or indirect DNA damaging properties.

Animals↗
PubMed1985

EcoA: the first member of a new family of type I restriction modification systems. Gene organization and enzymatic activities.

The characterization of the EcoA restriction-modification enzymes from Escherichia coli 15T- is described. The reactions catalysed by these enzymes are very similar to those catalysed by the classical type I restriction and modification enzymes, a family of genetically related proteins. The detailed mechanisms, particularly for DNA modification, differ. The genetic and transcriptional organizations are also very similar to those of the classical systems, despite the fact that EcoA is not allelic to the others. We demonstrate that the expression of the EcoA genes is controlled following conjugative transfer to other strains in such a way that no lethality is observed, probably because the recipient chromosome is completely modified before restriction activity is expressed.

Adenosine Triphosphate↗
PubMed2003

Detection and typing of Helicobacter pylori cagA/vacA genes by radioactive, one-step polymerase chain reaction in stool samples from children.

The detection and molecular typing of Helicobacter pylori virulence genes in human stool specimens by polymerase chain reaction (PCR) require an adequate amount of bacterial DNA and an appropriately adjusted PCR protocol. DNA was isolated from stool samples of 39 H. pylori-infected and nine uninfected Colombian children using the QIAamp Kit following the manufacturer's instructions but with modifications. DNA templates were amplified for the vacA s and m regions and for the cagA gene by PCR using radioactively labeled (32P) primers. The modifications in the standard Qiagen protocol of stool DNA extraction increased the final concentration of eluted total stool DNA 4.7 times (117 +/- 17 versus 22 +/- 3 ng/microl; P < 0.0001). Nevertheless, its amplification by regular PCR programs (30-40 cycles) did not generate visible signals because of the very low ratio of H. pylori DNA to other DNA. PCR for 80 cycles successfully amplified vacA in 36/39 samples (sensitivity, 92.3%) and cagA fragments in 21/39 (53.8%) fecal DNA samples. Both s and m vacA regions were amplified in 33/36 (91.7%) DNA samples. The s1m1 genotype was the most commonly isolated variant, accounting for 17/36 or 47.2% of positive samples. The s2m2 genotype was ascertained to be frequent also (14/36 or 38.9%). Almost all (94.1%) s1m1 genotypes were cagA positive. The majority of s2m2 genotypes (78.6%) were not associated with the cagA gene. Neither cagA nor vacA fragments were amplified from DNA isolates of H. pylori-uninfected children nor from DNA isolated from six gastrointestinal bacterial strains (specificity, 100%). The data suggest that the proposed modified technique of DNA extraction and PCR assay of stool samples may be an effective and reliable noninvasive tool for the detection and typing of H. pylori cagA/vacA virulence genes in infected individuals.

Antigens, Bacterial↗
PubMed1993

Effects of polychlorinated dibenzofurans on compounds in hepatic DNA of female Sprague-Dawley rats: structure dependence and mechanistic considerations.

Previous work indicated that covalent age-dependent DNA modifications of endogenous origin termed I-compounds may represent useful biomarkers for tumor promotion/carcinogenesis, as various tumor promoters/carcinogens, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and phenobarbital, reduce rat I-compound levels in liver, the target organ. The present study addressed the question as to whether polychlorinated dibenzofurans (PCDFs), which are related to TCDD and its congeners with regard to their toxic and biochemical properties, would also affect hepatic I-compound patterns and levels, and whether such effects would be chemical structure-dependent. Female Sprague-Dawley rats were treated once a week with a single dose (100 micrograms/kg) of 1,2,3,7,8-pentachlorodibenzofuran (1,2,3,7,8-PeCDF), 1,2,4,7,8-PeCDF, 2,3,4,7,8-PeCDF, or 2,3,4,6,7,8-hexachlorodibenzofuran (2,3,4,6,7,8-HeCDF) for 4 weeks and liver DNA was analyzed at the end of the last week by 32P-postlabeling assay. No carcinogen-DNA adducts were detected; however, levels of both non-polar and polar I-compounds were reduced in a structure-dependent manner. Potencies increased in the order, control (100%, 122 modifications in 10(9) DNA nucleotides = 1,2,4,7,8-PeCDF (104%) < 1,2,3,7,8-PeCDF (80%) < 2,3,4,7,8-PeCDF (61%) and 2,3,4,6,7,8-HeCDF (61%). Structure-activity relationships for total I-compounds, therefore, paralleled those reported for Ah receptor agonist activity, i.e., compounds that exhibit high cytosolic Ah receptor binding affinities and are also potent inducers of aryl hydrocarbon hydroxylase activity (1,2,3,7,8-PeCDF, 2,3,4,7,8-PeCDF, and 2,3,4,6,7,8-HeCDF) were active, while 1,2,4,7,8-PeCDF, which is a less potent Ah receptor agonist, was inactive. Polar I-compounds responded to a greater extent than did non-polar ones and, in general, individual I-compounds were affected differentially, thus decreased formation or increased removal of I-compounds played a role in the observed effects of the toxins on DNA. It is proposed that Ah receptor-mediated enzyme induction, particularly of cytochrome P450, is involved in reduced hepatic I-compound formation and that subnormal I-compound levels may contribute to tumor promotion.

Animals↗
PubMed2006

Analysis of sequence specificities of DNA-binding proteins with protein binding microarrays.

DNA-binding proteins are important for various cellular processes, such as transcriptional regulation, recombination, replication, repair, and DNA modification. Of particular interest are transcription factors (TFs), since through interactions with their DNA binding sites, they modulate gene expression in a manner required for normal cellular growth and differentiation, and also for response to environmental stimuli. To date, the DNA-binding specificities of most DNA-binding proteins remain unknown, as earlier technologies aimed at characterizing DNA-protein interactions have been laborious and not highly scalable. New DNA microarray-based technology, termed protein binding microarrays (PBMs), has been developed that allows rapid, high-throughput characterization of in vitro DNA binding site sequence specificities of TFs or of any DNA binding protein. DNA binding site data from PBMs can be used to predict what genes are regulated by a given TF, what the functions are of a given TF and its predicted target genes, and how that TF may fit into the transcriptional regulatory networks of the cell.

Animals↗
PubMed1999

Prostaglandin H synthase-medicated oxidation and binding to DNA of a detoxication metabolite of carcinogenic Sudan I, 1-(phenylazo)-2,6-dihydroxynaphthalene.

The metabolite of the carcinogenic azo dye Sudan I, 1-(phenylazo)-2,6-dihydroxynaphthalene (6-OH-Sudan I), which is considered to be the detoxification product of this dye is metabolized by prostaglandin H synthase (PHS) in the presence of arachidonic acid or H2O2 in vitro. The apparent Michaelis constant value for 6-OH-Sudan I as a substrate is 98.9 microM. 1-(Phenylazo)-2,6-naphthoquinone is a principal product of the 6-OH-Sudan I oxidation. This oxidation is inhibited by radical scavengers nitrosobenzene, ascorbate, glutathione and NADH. This indicates that PHS metabolizes 6-OH-Sudan I through a one-electron oxidation mechanism, giving rise to free radicals. During the PHS-mediated reaction, 6-OH-Sudan I is activated to metabolites binding to protein and DNA. The 32P-postlabeling analysis of DNA modified by activated 6-OH-Sudan I provides evidence that covalent binding to DNA is the principal type of DNA modification. The PHS-mediated binding of 6-OH-Sudan I to DNA presumably proceeds through formation of 1-(phenylazo)-2,6-naphthoquinone. The results suggest strongly that the C-hydroxylated derivative of Sudan I (6-OH-Sudan I) should be evaluated as a proximate carcinogenic metabolite, which may participate in the initiation of Sudan I-carcinogenesis in the urinary bladder.

Animals↗
PubMed1998

CpG methylation within the 5' regulatory region of the BRCA1 gene is tumor specific and includes a putative CREB binding site.

Breast cancer is a genetic disease arising from a series of germ-line and/or somatic DNA changes in a variety of genes, including BRCA1 and BRCA2. DNA modifications have been shown to occur by a number of mechanisms that include DNA methylation. In some cases, the aberrant methylation of CpGs within 5' regulatory regions has led to suppression of gene activity. In this report we describe a variation in the pattern of DNA methylation within the regulatory region of the BRCA1 gene. We found no evidence of methylation at CpGs within the BRCA1 promoter in a variety of normal human tissues. However, screening of a series of randomly sampled breast carcinomas revealed the presence of CpG methylation adjacent to the BRCA1 transcription start site. One such methylated CpG occurs at a putative CREB (cAMP-responsive element binding) transcription factor binding site in the BRCA1 promoter. Gelshift assays with methylated and unmethylated BRCA1/CREB binding site oligonucleotides demonstrate that this site is sensitive to site-specific CpG methylation. These data suggest that aberrant DNA methylation at regulatory sequences in the BRCA1 locus may play a role in the transcriptional inactivation of the BRCA1 gene within subclones of breast tumors. This study represents the first evidence suggesting a role for DNA methylation in the transcriptional inactivation of the BRCA1 in human breast cancer.

Base Sequence↗
PubMed2006

Genome-wide location analysis: insights on transcriptional regulation.

Gene expression analysis of microarray data can provide a global view of the transcriptome of a cell or specific tissue type, revealing important information about the kinds of signaling pathways, genes and protein classifications that are active. However, transcript profiles alone do not reveal how expression levels are controlled or which transcription factors (TFs) are responsible. Establishing transcriptional regulatory networks requires knowledge of TFs bound to promoter, enhancer and repressor elements. Accessibility of these sites and an additional level of control are mediated by chromatin and DNA modifications. Genome-wide location analysis is a tool for identifying protein-DNA interaction sites on a genomic scale. Applications of this tool are proving invaluable in determining in vivo target genes of TFs, epigenetic marks and cis-regulatory elements. Here, we will discuss how advances have been made in each of these categories and how this has helped to elucidate regulatory networks and control mechanisms.

Animals↗
PubMed1995

Studies of DNA methylation in animals.

We have been studying the evolution and function of DNA methylation in vertebrate animals using three related approaches. The first is to further characterise proteins that bind to methylated DNA. Such proteins can be viewed as 'receptors' of the methyl-CpG 'ligand' that mediate downstream consequences of DNA modification. The second approach involves CpG islands. These patches of non-methylated DNA coincide with most gene promoters, but their origin and functional significance have only recently become the subject of intensive study. The third approach is to trace the evolution of DNA methylation. Genomic methylation patterns of vertebrates are strikingly different from those of invertebrates. By studying methylation in animals that diverged from common ancestors near to the invertebrate/vertebrate boundary, we will assess the possibility that changes in DNA methylation contributed causally to the evolution of the complex vertebrate lineage.

Animals↗
PubMed1998

Recognition of core-type DNA sites by lambda integrase.

Escherichia coli phage lambda integrase (Int) is a 40 kilodalton, 356 amino acid residue protein, which belongs to the lambda Int family of site-specific recombinases. The amino-terminal domain (residues 1 to 64) of Int binds to "arm-type" DNA sites, distant from the sites of DNA cleavage. The carboxy-terminal fragment, termed C65 (residues 65 to 356), binds "core-type" DNA sites and catalyzes cleavage and ligation at these sites. It has been further divided into two smaller domains, encompassing residues 65 to 169 and 170 to 356, respectively. The latter has been characterized and its crystal structure has been determined. Although this domain catalyzes the cleavage and rejoining of DNA strands it, unexpectedly, does not form electrophorectically stable complexes with core-type DNA. Here we have investigated the critical features of lambda Int binding to core-type DNA sites; especially, the role of the central 65 to 169 domain. To eliminate the complexities arising from lambda Int's heterobivalency we studied Int C65, which was shown to be as competent as Int, in binding to, and cleaving, core-type sites. Zero-length UV crosslinking was used to show that Ala125 and Ala126 make close contact with bases in the core-type DNA. Modification by pyridoxal 5'-phosphate was used to identify Lys103 at the protein-DNA interface. Since both of the identified loci are in the central domain, it was cloned and purified and found to bind to core-type DNA autonomously and specifically. The synergistic roles of the catalytic and the central, or core-binding (CB), domains in the interaction with core-type DNA are discussed for (Int and related DNA recombinases.

Bacteriophage lambda↗
PubMed1995

32P-postlabelling analysis of adducts formed by mitoxantrone and ametantrone with DNA and homopolydeoxyribonucleotides after enzymatic activation.

DNA adduct formation by enzymatically activated mitoxantrone and ametantrone has been studied by 32P-postlabelling method. Both drugs were activated by peroxidase/hydrogen peroxide system and formed several DNA adducts when reacted with calf thymus DNA. Mitoxantrone gave 3 and ametantrone 4 different DNA adducts with apparently similar chromatographic features suggesting that DNA adducts formed by both compounds do not differ significantly in their chemical structure. Despite this similarity, the level of DNA modification is 10 times higher for mitoxantrone compared to ametantrone. We did not observe DNA adducts in control samples where both drugs were incubated with DNA in the absence of the activating system. It indicates the importance of oxidative activation of mitoxantrone and ametantrone for their ability to bind covalently DNA. In order to identify nucleobases involved in the formation of DNA adducts by anthracenediones, polydeoxyadenosine, polydeoxythymidine, deoxyguanosine 3'-monophosphate and deoxycytosine 3'-monophosphate were modified by mitoxantrone and ametantrone activated in the above mentioned oxidating system. We proved that the only nucleobase modified by both drugs is guanine with no alkylation observed at other DNA bases. The pattern of adducts formed with deoxyguanosine 3'-monophosphate is reminiscent of that obtained with calf thymus DNA. In addition, mitoxantrone was found to be phosphorylated during the postlabelling procedure, most probably at the 1,4-hydroxyl groups of the chromophore. Ametantrone which does not possess hydroxyl groups attached to the chromophore core was resistant to phosphorylation by T4 polynucleotide kinase and gamma-[32P]ATP. These results for the first time provide direct evidence that mitoxantrone and ametantrone form DNA adducts when activated by oxidation in vitro.

Animals↗
PubMed2005

DNA single strands tethered to fused quartz/water interfaces studied by second harmonic generation.

Second harmonic generation (SHG) is used to study oligonucleotides at aqueous/solid interfaces for the first time. Detailed thermodynamic state information for interfacial DNA single strands, namely, the interfacial charge density, the interfacial potential, and the change in the interfacial energy density, is obtained. The phosphate groups on the DNA backbone serve as intrinsic labels that do not require DNA modification other than surface attachment. This approach is broadly applicable for the investigation of DNA during its interaction with biological targets, as well as charged biopolymers in general, and has important implications for predicting and controlling macromolecular interactions, improving biodiagnostics, and understanding life processes.

Cross-Linking Reagents↗
PubMed1981

DNA methylation by N-nitrosomethylbenzylamine in target and non-target tissues of NMRI mice.

Adult female NMRI mice received a single i.p injection of N-nitroso(methyl-14C)methylbenzylamine (2.5 mg/kg body weight). Multiple weekly applications of such a dose, by this route, have previously been shown to induce lung adenomas and forestomach carcinomas in all experimental animals. After a survival time of 6 h, DNA was isolated from various tissues and analysed for methylated purines by separation of the acid hydrolysate on Sephasorb columns. Highest concentrations of 7-methylguanine and 06-methylguanine were present in hepatic DNA, followed by lung and forestomach. DNA methylation in the oesophagus was only 21% less than in forestomach. Since both tissues develop a high tumour incidence after oral administration of N-nitrosomethylbenzylamine (MBN), this observation suggests that despite their anatomical similarities the level of DNA modification required for malignant transformation differs considerably in these tissue. In the remaining organs, DNA alkylation was either considerably less (colon, glandular stomach, kidney) or not detectable (small intestine, spleen). These date indicate that following i.p. injection in mice, MBN is preferentially metabolised in a non-target organ (liver). Among the various other tissues investigated, highest levels of initial DNA methylation were present in forestomach and lung, i.e., the principal target organs of MBN for this route of application.

Animals↗
PubMed1985

Target organ-specific covalent DNA damage preceding diethylstilbestrol-induced carcinogenesis.

The synthetic estrogen diethylstilbestrol (DES), a known human carcinogen, induces renal carcinoma in male Syrian hamsters within 6 months after s.c. implantation. Tumor formation could be evoked by its hormonal properties or by a reactive genotoxic metabolite binding to DNA, but previous attempts to detect adducts have failed. In the present study, kidney DNA of male Syrian hamsters, treated with s.c. DES implants to induce renal carcinoma, was analyzed for the presence of DES-induced adducts using 32P-postlabeling assay. Covalently-modified DNA nucleotides were detected in the kidneys after chronic DES treatment, but not in kidneys of untreated hamsters, or in liver or tumor tissue of DES-treated animals. This report demonstrates for the first time the ability of an estrogen to give rise to covalent DNA modification in vivo specifically in the target organ of carcinogenesis. DES-induced covalent DNA adducts are taken as evidence for tumor initiation by DES via damage to cellular macromolecules, in addition to tumor-promotional effects described previously.

Adenosine Triphosphate↗