Induction of AT-specific DNA-interstrand crosslinks by bizelesin in genomic and simian virus 40 DNA. (1/2171)

Bizelesin is a bifunctional AT-specific DNA alkylating drug. Our study characterized the ability of bizelesin to induce interstrand crosslinks, a potential lethal lesion. In genomic DNA of BSC-1 cells, bizelesin formed from approx. 0.3 to 6.03+/-0.85 interstrand crosslinks per 106 base pairs, at 5-100 nM drug concentration, respectively, comparable to the number of total adducts previously determined in the same system (J.M. Woynarowski, M.M. McHugh, L.S. Gawron, T.A. Beerman, Biochemistry 34 (1995) 13042-13050). Bizelesin did not induce DNA-protein crosslinks or strand breaks. A model defined target, intracellular simian virus 40 (SV40) DNA, was employed to map at the nucleotide level sites of bizelesin adducts, including potential interstrand crosslinks. Preferential adduct formation was observed at AT tracts which are abundant in the SV40 matrix associated region and the origin of replication. Many sites, including each occurrence of 5'-T(A/T)4A-3', co-mapped on both DNA strands suggesting interstrand crosslinks, although monoadducts were also formed. Bizelesin adducts in naked SV40 DNA were found at similar sites. The localization of bizelesin-induced crosslinks in AT-rich tracts of replication-related regions is consistent with the potent anti-replicative properties of bizelesin. Given the apparent lack of other types of lesions in genomic DNA, interstrand crosslinks localized in AT-rich tracts, and to some extent perhaps also monoadducts, are likely to be lethal effects of bizelesin.  (+info)

The effect of cotinine or cigarette smoke co-administration on the formation of O6-methylguanine adducts in the lung and liver of A/J mice treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) (2/2171)

4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific nitrosamine, induces lung adenomas in A/J mice, following a single intraperitoneal (i.p.) injection. However, inhalation of tobacco smoke has not induced or promoted tumors in these mice. NNK-induced lung tumorigenesis is thought to involve O6-methylguanine (O6MeG) formation, leading to GC-->AT transitional mispairing and an activation of the K-ras proto-oncogene in the A/J mouse. NNK can be metabolized by several different cytochromes P450, resulting in a number of metabolites. Formation of the promutagenic DNA adduct O6MeG is believed to require metabolic activation of NNK by cytochrome P450-mediated alpha-hydroxylation of the methylene group adjacent to the N-nitroso nitrogen to yield the unstable intermediate, methanediazohydroxide. Nicotine, cotinine (the major metabolite of nicotine), and aqueous cigarette tar extract (ACTE) have all been shown to effectively inhibit metabolic activation of NNK to its mutagenic form, most likely due to competitive inhibition of the cytochrome P450 enzymes involved in alpha-hydroxylation of NNK. The objective of the current study was to monitor the effects of cotinine and cigarette smoke (CS) on the formation of O6MeG in target tissues of mice during the acute phase of NNK treatment. To test the effect of cotinine, mature female A/J mice received a single intraperitoneal injection of NNK (0, 2.5, 5, 7.5, or 10 mumole/mouse) with cotinine administered at a total dose of 50 mumole/mouse in 3 separate i.p. injections, administered 30 min before, immediately after, and 30 min after NNK treatment. To test the effect of whole smoke exposure on NNK-related O6MeG formation, mice were exposed to smoke generated from Kentucky 1R4F reference cigarettes at 0, 0.4, 0.6, or 0.8 mg wet total particulate matter/liter (WTPM/L) for 2 h, with a single i.p. injection of NNK (0, 3.75, or 7.5 mumole/mouse) midway through the exposure. Cigarette smoke alone failed to yield detectable levels of O6MeG. The number of O6MeG adducts following i.p. injection of NNK was significantly (p < 0.05) reduced in both lung and liver by cotinine and by cigarette smoke exposure. Our results demonstrate that NNK-induced O6MeG DNA adducts in A/J mice are significantly reduced when NNK is administered together with either cotinine, the major metabolite of nicotine, or the parental complex mixture, cigarette smoke.  (+info)

Effect of cellular ATP depletion on topoisomerase II poisons. Abrogation Of cleavable-complex formation by etoposide but not by amsacrine. (3/2171)

Topoisomerase (topo) II poisons have been categorized into ATP-independent and -dependent drugs based on in vitro studies. We investigated drug-induced topoII-DNA complexes in intact cells almost completely depleted of ATP. Virtually no DNA single-strand breaks (SSBs), as measured by alkaline elution, were detected in energy-depleted cells treated with the topoII poisons etoposide, teniposide, daunorubicin, doxorubicin, mitoxantrone, or clerocidin. This inhibition was reversible; subsequent incubation with glucose restored the level of DNA SSBs. The effect of ATP depletion was specific for topoII, because topoI-mediated cleavable complexes induced by camptothecin were unaffected by ATP depletion. Furthermore, etoposide-induced DNA-protein complexes and DNA double-strand breaks, as measured by filter elution techniques, and topoIIalpha and -beta trapping, as measured by a band depletion assay, were completely inhibited by energy depletion. Differences in drug transport could not explain the effect of ATP depletion. The topoII poison amsacrine (m-AMSA) was unique with respect to ATP dependence. In ATP-depleted cells, m-AMSA-induced DNA SSBs, DNA double-strand breaks, DNA-protein complexes, topoIIalpha and -beta trapping were only modestly reduced. The accumulation of m-AMSA was reduced in ATP-depleted cells, which indicates that drug transport could contribute to the modest decrease in m-AMSA-induced cleavable complexes. In conclusion, drug-induced topoII-DNA complexes were completely antagonized in ATP-depleted cells, except in the case of m-AMSA. One possible interpretation is that m-AMSA mainly produces prestrand passage DNA lesions, whereas the other topoII poisons tested exclusively stabilize poststrand passage DNA lesions in intact cells.  (+info)

A novel trinuclear platinum complex overcomes cisplatin resistance in an osteosarcoma cell system. (4/2171)

Multinuclear platinum compounds have been designed to circumvent the cellular resistance to conventional platinum-based drugs. In an attempt to examine the cellular basis of the preclinical antitumor efficacy of a novel multinuclear platinum compound (BBR 3464) in the treatment of cisplatin-resistant tumors, we have performed a comparative study of cisplatin and BBR 3464 in a human osteosarcoma cell line (U2-OS) and in an in vitro selected cisplatin-resistant subline (U2-OS/Pt). A marked increase of cytotoxic potency of BBR 3464 in comparison with cisplatin in U2-OS cells and a complete lack of cross-resistance in U2-OS/Pt cells were found. A detailed analysis of the cisplatin-resistant phenotype indicated that it was associated with reduced cisplatin accumulation, reduced interstrand cross-link (ICL) formation and DNA platination, microsatellite instability, and reduced expression of the DNA mismatch repair protein PMS2. Despite BBR 3464 charge and molecular size, in U2-OS and U2-OS/Pt cells, BBR 3464 accumulation and DNA-bound platinum were much higher than those observed for cisplatin. In contrast, the frequency of ICLs after exposure to BBR 3464 was very low. The time course of ICL formation after drug removal revealed a low persistence of these types of DNA lesions induced by BBR 3464, in contrast to an increase of DNA lesions induced by cisplatin, suggesting that components of the DNA repair pathway handle the two types of DNA lesions differently. The cellular response of HCT116 mismatch repair-deficient cells was consistent with a lack of influence of mismatch repair status on BBR 3464 cytotoxicity. Because BBR 3464 produces high levels of lesions different from ICLs, likely including intra-strand cross-links and monoadducts, the ability of the triplatinum complex to overcome cisplatin resistance appears to be related to a different mechanism of DNA interaction (formation of different types of drug-induced DNA lesions) as compared with conventional mononuclear complexes rather than the ability to overcome specific cellular alterations.  (+info)

Biomarkers for exposure to ambient air pollution--comparison of carcinogen-DNA adduct levels with other exposure markers and markers for oxidative stress. (5/2171)

Human exposure to genotoxic compounds present in ambient air has been studied using selected biomarkers in nonsmoking Danish bus drivers and postal workers. A large interindividual variation in biomarker levels was observed. Significantly higher levels of bulky carcinogen-DNA adducts (75.42 adducts/10(8) nucleotides) and of 2-amino-apidic semialdehyde (AAS) in plasma proteins (56.7 pmol/mg protein) were observed in bus drivers working in the central part of Copenhagen, Denmark. In contrast, significantly higher levels of AAS in hemoglobin (55.8 pmol/mg protein), malondialdehyde in plasma (0. 96 nmol/ml plasma), and polycyclic aromatic hydrocarbon (PAH)-albumin adduct (3.38 fmol/ microg albumin) were observed in the suburban group. The biomarker levels in postal workers were similar to the levels in suburban bus drivers. In the combined group of bus drivers and postal workers, negative correlations were observed between bulky carcinogen-DNA adduct and PAH-albumin levels (p = 0.005), and between DNA adduct and [gamma]-glutamyl semialdehyde (GGS) in hemoglobin (p = 0.11). Highly significant correlations were found between PAH-albumin adducts and AAS in plasma (p = 0.001) and GGS in hemoglobin (p = 0.001). Significant correlations were also observed between urinary 8-oxo-7, 8-dihydro-2'-deoxyguanosine and AAS in plasma (p = 0.001) and PAH-albumin adducts (p = 0.002). The influence of the glutatione S-transferase (GST) M1 deletion on the correlation between the biomarkers was studied in the combined group. A significant negative correlation was only observed between bulky carcinogen-DNA adducts and PAH-albumin adducts (p = 0.02) and between DNA adduct and urinary mutagenic activity (p = 0.02) in the GSTM1 null group, but not in the workers who were homozygotes or heterozygotes for GSTM1. Our results indicate that some of the selected biomarkers can be used to distinguish between high and low exposure to environmental genotoxins.  (+info)

Detection of benzo[a]pyrene diol epoxide-DNA adducts in embryos from smoking couples: evidence for transmission by spermatozoa. (6/2171)

Tobacco smoking is deleterious to reproduction. Benzo[a]pyrene (B[a]P) is a potent carcinogen in cigarette smoke. Its reactive metabolite induces DNA-adducts, which can cause mutations. We investigated whether B[a]P diol epoxide (BPDE) DNA adducts are detectable in preimplantation embryos in relation to parental smoking. A total of 17 couples were classified by their smoking habits: (i) both partners smoke; (ii) wife non-smoker, husband smokes; and (iii) both partners were non-smokers. Their 27 embryos were exposed to an anti-BPDE monoclonal antibody that recognizes BPDE-DNA adducts. Immunostaining was assessed in each embryo and an intensity score was calculated for embryos in each smoking group. The proportion of blastomeres which stained was higher for embryos of smokers than for non-smokers (0.723 versus 0.310). The mean intensity score was also higher for embryos of smokers (1.40+/-0.28) than for non-smokers (0.38+/-0.14; P = 0.015), but was similar for both types of smoking couples. The mean intensity score was positively correlated with the number of cigarettes smoked by fathers (P = 0.02). Increased mean immunostaining in embryos from smokers, relative to non-smokers, indicates a relationship with parental smoking. The similar levels of immunostaining in embryos from both types of smoking couples suggest that transmission of modified DNA is mainly through spermatozoa. We confirmed paternal transmission of modified DNA by detection of DNA adducts in spermatozoa of a smoker father and his embryo.  (+info)

In vitro reactions of butadiene monoxide with single- and double-stranded DNA: characterization and quantitation of several purine and pyrimidine adducts. (7/2171)

We have previously shown that butadiene monoxide (BM), the primary metabolite of 1,3-butadiene, reacted with nucleosides to form alkylation products that exhibited different rates of formation and different stabilities under in vitro physiological conditions. In the present study, BM was reacted with single-stranded (ss) and double-stranded (ds) calf thymus DNA and the alkylation products were characterized after enzymatic hydrolysis of the DNA. The primary products were regioisomeric N-7-guanine adducts. N-3-(2-hydroxy-3-buten-1-yl)adenine and N-3-(1-hydroxy-3-buten-2-yl)adenine, which were depurinated from the DNA more rapidly than the N-7-guanine adducts, were also formed. In addition, N6-(2-hydroxy-3-buten-1-yl)deoxyadenosine and N6-(1-hydroxy-3-buten-2-yl)deoxyadenosine were detected and evidence was obtained that these adducts were formed by Dimroth rearrangement of the corresponding N-1-deoxyadenosine adducts, not while in the DNA, but following the release of the N-1-alkylated nucleosides by enzymatic hydrolysis. N-3-(2-hydroxy-3-buten-1-yl)deoxyuridine adducts, which were apparently formed subsequent to deamination reactions of the corresponding deoxycytidine adducts, were also detected and were stable in the DNA. Adduct formation was linearly dependent upon BM concentration (10-1000 mM), with adduct ratios being similar at the various BM concentrations. At a high BM concentration (750 mM), the adducts were formed in a linear fashion for up to 8 h in both ssDNA and dsDNA. However, the rates of formation of the N-3-deoxyuridine and N6-deoxyadenosine adducts increased 10- to 20-fold in ssDNA versus dsDNA, whereas the N-7-guanine adducts increased only slightly, presumably due to differences in hydrogen bonding in ssDNA versus dsDNA. These results may contribute to a better understanding of the molecular mechanisms of mutagenesis and carcinogenesis of both BM and its parent compound, 1,3-butadiene.  (+info)

Idoxifene derivatives are less reactive to DNA than tamoxifen derivatives, both chemically and in human and rat liver cells. (8/2171)

The drug tamoxifen shows evidence of genotoxicity, and induces liver tumours in rats. Covalent DNA adducts have been detected in the liver of rats treated with tamoxifen, and these arise through metabolism at the alpha-position to give an ester which reacts with DNA. (E)-1-(4-iodophenyl)-2-phenyl-1-[4-(2-pyrrolidinoethoxy)phenyl]-but-1-en e (idoxifene) is an analogue of tamoxifen in which formation of DNA adducts is greatly reduced; we could not detect any adducts in the DNA of cultured rat hepatocytes treated with 10 microM idoxifene, after analysis by the 32P-post-labelling method. The metabolite (Z)-4-(4-iodophenyl)-4-[4-(2-pyrrolidinoethoxy)phenyl]-3-phenyl-3-but en-2-ol (alpha-hydroxyidoxifene) gave adducts in rat hepatocytes, but far fewer than the corresponding tamoxifen metabolite. In human hepatocytes, neither idoxifene nor tamoxifen induced detectable levels of DNA adducts. We prepared the alpha-acetoxy ester of idoxifene as a model for the ultimate reactive metabolite formed in rat liver. It was less reactive than alpha-acetoxytamoxifen, as might be expected on mechanistic grounds. It reacted with DNA in the same way, to give adducts which were probably N2-alkyldeoxyguanosines, but to a lower extent. All these results indicate that idoxifene is much less genotoxic than tamoxifen, and should therefore be a safer drug.  (+info)

DNA adducts are researched in laboratory settings. A typical experimental design for studying DNA adducts is to induce them ... forming DNA adducts, and inducing double-strand breaks (DSBs). In regards to DNA adduct formation, this analysis was conducted ... Ongoing research on DNA adducts seeks to overcome these complications. It is the hope that in future medical practices DNA ... In molecular genetics, a DNA adduct is a segment of DNA bound to a cancer-causing chemical. This process could lead to the ...
"Mitosene-DNA Adducts. Characterization of Two Major DNA Monoadducts Formed by 1,10-Bis(acetoxy)-7-methoxymitosene upon ...
... ions are often formed in a mass spectrometer ion source. Adductomics DNA adduct IUPAC, Compendium of Chemical ... Adducts often form between Lewis acids and Lewis bases. A good example is the formation of adducts between the Lewis acid ... Adducts are not necessarily molecular in nature. A good example from solid-state chemistry is the adducts of ethylene or carbon ... An adduct ion is formed from a precursor ion and contains all of the constituent atoms of that ion as well as additional atoms ...
These adducts may then produce DNA crosslinks. Glycation of DNA may also lead to mutation, breaks in DNA and cytotoxicity. In ... Formation mechanism of glyoxal-DNA adduct, a DNA cross-link precursor. Int J Biol Macromol. 2017 May;98:664-675. doi: 10.1016/j ... Guanine bases in DNA can undergo non-enzymatic glycation by glyoxal to form glyoxal-guanine adducts. ...
... reacts with DNA to form adducts. It is more reactive toward DNA than acrylamide. Several glycidamide-DNA adducts ... The main DNA adducts are N7-(2-carbamoyl-2-hydroxyethyl)-guanine (or N7-GA-Gua) and N3-(2-carbamoyl-2-hydroxyethyl)adenine (or ... Mice and rats show mutations and DNA adducts consistent with those arising from glycidamide. Another study found tumors in the ... ISBN 978-1-4419-3672-1. Bergmark, E., Calleman, C. J., & Costa, L. G. (1991). Formation of hemoglobin adducts of acrylamide and ...
LTA4 can form adducts with tissue DNA. Other reactions of lipoxygenases generate cellular damage; murine models implicate 15- ... PGs and LTs may signal or regulate DNA-transcription there; LTB4 is ligand for PPARĪ±.(See diagram at PPAR). Both COX1 and COX2 ...
Liu XY, Zhu MX, Xie JP (2010). "Mutagenicity of acrolein and acrolein-induced DNA adducts". Toxicol. Mech. Methods. 20 (1): 36- ... Tompkins EM, McLuckie KI, Jones DJ, Farmer PB, Brown K (2009). "Mutagenicity of DNA adducts derived from ethylene oxide ... Kastan MB (2008). "DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes Memorial Award Lecture". Mol ... The most important chemicals causing cancer are those that produce DNA damage, since such damage appears to be the primary ...
Liu XY, Zhu MX, Xie JP (2010). "Mutagenicity of acrolein and acrolein-induced DNA adducts". Toxicol. Mech. Methods. 20 (1): 36- ... Tompkins EM, McLuckie KI, Jones DJ, Farmer PB, Brown K (2009). "Mutagenicity of DNA adducts derived from ethylene oxide ... Kastan MB (2008). "DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes Memorial Award Lecture". Mol ... The most important chemicals causing cancer are those that produce DNA damage since such damage appears to be the primary ...
Liu XY, Zhu MX, Xie JP (2010). "Mutagenicity of acrolein and acrolein-induced DNA adducts". Toxicol. Mech. Methods. 20 (1): 36- ... Tompkins EM, McLuckie KI, Jones DJ, Farmer PB, Brown K (2009). "Mutagenicity of DNA adducts derived from ethylene oxide ... Kastan MB (2008). "DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes Memorial Award Lecture". Mol ... The most important chemical compounds causing cancer are those that produce DNA damage since such damage appears to be the ...
CG adduct destabilizes the helix and induces a bend and twist in the DNA. DNA crosslinking lesions can also be formed when ... intrastrand DNA crosslinks, interstrand DNA crosslinks, and DNA-protein crosslinks. When cisplatin generates DNA crosslinks, it ... Cancer treatments have been engineered using DNA cross-linking agents to interact with nitrogenous bases of DNA to block DNA ... These adducts result in local distortions to DNA at the site of intercalation. Psoralens are used in the medical treatment of ...
... s can also form adducts with DNA by a single covalent bond through an aminal linkage from the 3'-amino of ... Cutts SM, Nudelman A, Rephaeli A, Phillips DR (February 2005). "The power and potential of doxorubicin-DNA adducts". IUBMB Life ... The supply of extracellular formaldehyde using formaldehyde-releasing prodrugs can promote covalent DNA adduct formation. Such ... Anthracyclines intercalated into DNA, form a stable anthracycline-DNA-topoisomerase II ternary complex thus "poisoning" the ...
... causes DNA damage, which is thought to be mediated by formation of DNA adducts. In this process, 4- ... A linear correlation was found between adduct levels and the occurrence of liver tumors in female mice by comparing DNA adducts ... The compound can be metabolized by humans which the product may form adducts with DNA in human urothelial mucosa and bladder ... The final products of this metabolism are aryl nitrenium ions which form DNA adducts. During this process reactive oxygen ...
... forms monofunctional adducts with guanosine residues in the DNA. The large and hydrophobic nature of the ... "Effect of a Monofunctional Phenanthriplatin-DNA Adduct on RNA Polymerase II Transcriptional Fidelity and Translesion Synthesis ... a major protein used by the cell to transcribe DNA. Since transcription is essential for DNA synthesis and gene expression, ... A study examining the effects of monofunctional adducts on bacterial growth reported a significant decrease in Escherichia coli ...
These groups can ultimately form an adduct with the base of a nucleotide in the DNA. DNA adducts with PAHs can disrupt the DNA ... Baird, W. M.; Hooven, L. A.; Mahadevan, B. (2015). "Carcinogenic polycyclic aromatic hydrocarbon-DNA adducts and mechanism of ... replication or modify the DNA, by removing bases like adenine and guanine from the nucleotides. This can in the end lead to ...
A DNA adduct is a segment of DNA that binds to a chemical carcinogen. Some adducts that cause lesions to DNA included ... MDA reacts with DNA to form the M1dG adduct which causes DNA lesions. Many systems are in place to repair DNA and RNA lesions ... ROS is one of the major endogenous sources of DNA damage and the most studied oxidative DNA adduct is 8-oxo-dG. Other adducts ... These epoxy aldehydes can damage DNA by producing etheno adducts. An increase in this type of DNA lesion exhibits conditions ...
DNA Adducts by the Mammalian Excision Nuclease". Biochemistry. 35 (31): 10004-10013. doi:10.1021/bi960453+. ISSN 0006-2960. ... "HMG-domain proteins specifically inhibit the repair of the major DNA adduct of the anticancer drug cisplatin by human excision ... "Cisplatin and DNA repair in cancer chemotherapy". Trends in Biochemical Sciences. 20 (10): 435-439. doi:10.1016/S0968-0004(00) ...
Stable adducts may lead to DNA replication errors, while unstable adducts react with the DNA strand, removing a purine base ( ... These metabolites can bind to DNA at specific sites, forming bulky complexes called DNA adducts that can be stable or unstable ... This enzyme then metabolically processes the PAHs to quinone metabolites that bind to DNA in reactive adducts that remove ... Baird, W. M.; Hooven, L. A.; Mahadevan, B. (2015-02-01). "Carcinogenic polycyclic aromatic hydrocarbon-DNA adducts and ...
... reacts with DNA in vitro. The major DNA adduct formed in this reaction is identified as the 8-(phenylazo)guanine adduct, which ... Guanosine DNA adducts derived from peroxidase metabolites of Sudan 1 were also found in vivo in the bladder of rats. The ... As a consequence DNA, RNA and protein adducts are formed. (See figure 2). Therefore, peroxidase-catalyzed activation of Sudan I ... Hence, formation of adducts of Sudan I reactive species with nucleophilic species, such as DNA, tRNA, proteins, polynucleotides ...
... which can damage DNA). The level of oxidative stress and acetaldehyde-induced DNA adducts due to alcohol consumption does not ... Oxidative DNA damage is mutagenic and also causes epigenetic alterations at the sites of DNA repair. Epigenetic alterations and ... "Formation of acetaldehyde-derived DNA adducts due to alcohol exposure". Chemico-Biological Interactions. 188 (3): 367-75. doi: ... The excess deoxycholic acid causes DNA damage and inflammation in the liver, which, in turn, can lead to liver cancer. Several ...
PhIP has been shown to induce DNA adducts and mutations. These adducts have been found in a wide variety of sensitive tissues ... DNA and protein adducts were formed in the colon and blood. However, the adducts were unstable and declined over a 24-hour ... 1999). DNA and protein adduct formation in the colon and blood of humans after exposure to a dietary-relevant dose of 2-amino-1 ... PhIP has also formed DNA adducts in vivo in both rats and monkeys. PhIP has been tested for carcinogenicity in both mice and ...
In rats gavaged with riddelliine, a set of DNA adducts of dehydroretronecine (DHS) in liver DNA can serve as biomarkers for the ... the resulting carbocation can bind to two DNA bases, producing another cross-linked DNA adduct. In both cases, the covalently ... To date, 8 DHP-derived DNA adducts have been observed, all of which contribute to the tumorigenicity of riddelliine. ... Two possible pathways emerge from this cytotoxic intermediate, both of which produce similar tumorigenic DNA adducts. Neither ...
... which can form DNA-base adducts, thus giving aristolochic acid I its mutagenic properties. Aristolactam I adducts that are ... Nephropathy caused by aristolochic acid consumption is not mechanistically understood, but DNA adducts characteristic of ... "Exceptionally long-term persistence of DNA adducts formed by carcinogenic aristolochic acid I in renal tissue from patients ... have AAN can be confirmed through phytochemical analysis of plant products consumed and detection of aristolactam DNA adducts ...
Acetaldehyde can react with DNA to create DNA adducts including the Cr-Pdg adduct. This Cr-PdG adduct "is likely to play a ... Brooks P, Theruvathu J, Cho CH, Purohit V (2006). "Acetaldehyde-DNA Adducts: Implications for the Molecular Mechanism of ... owing to its multiple mutagenic effects on DNA." ...
M1dG is the major endogenous DNA adduct in humans. M1dG adducts have been detected in cell DNA in liver, leucocytes, pancreas ... of a specific type of DNA adduct called M1dG. The M1dG adduct in turn is formed by a condensation reaction between guanosine ... Detection and quantification of M1dG adducts in the body as measured by free M1G is a tool for detecting DNA damage that may ... "Metabolism in vitro and in vivo of the DNA base adduct, M1G". Chem. Res. Toxicol. 20 (3): 550-7. doi:10.1021/tx600334x. PMID ...
"bulky adduct formation" (e.g., benzo[a]pyrene diol epoxide-dG adduct, aristolactam I-dA adduct) mismatch of bases, due to ... Reduced expression of DNA repair genes causes deficient DNA repair. When DNA repair is deficient DNA damages remain in cells at ... Biology portal Accelerated aging disease Aging DNA Cell cycle DNA damage (naturally occurring) DNA damage theory of aging DNA ... Human DNA Repair Genes 3D structures of some DNA repair enzymes Human DNA repair diseases DNA repair special interest group DNA ...
"Endogenous versus Exogenous DNA Adducts: Their Role in Carcinogenesis, Epidemiology, and Risk Assessment". Toxicological ... the majority of formaldehyde-DNA adducts found in non-respiratory tissues are derived from endogenously produced formaldehyde. ... Formaldehyde and its adducts are ubiquitous in living organisms because they are produced naturally. Food may contain ... In yeast, formaldehyde is found to perturb pathways for DNA repair and cell cycle. In the residential environment, formaldehyde ...
Metabolites of aristolochic acid enter the cell nucleus and form adducts on DNA. While adducts on the transcribed DNA strand ... the adducts on the non-transcribed strand remain and eventually cause DNA replication errors. These adducts have a preference ... "Aristolactam I a metabolite of aristolochic acid I upon activation forms an adduct found in DNA of patients with Chinese herbs ... "Aristolactam I a metabolite of aristolochic acid I upon activation forms an adduct found in DNA of patients with Chinese herbs ...
These diol-epoxides covalently bind with DNA base pairs, most often with guanine and adenine to form stable adducts within the ... One mechanism of action for genotoxic carcinogens includes the formation of DNA adducts. Once the PAH compound enters an ... A biological target, also known as the site of action, can be binding proteins, ion channels, DNA, or a variety of other ... Since these toxicants do not directly act on DNA, little is known about the mechanistic pathway. It has been proposed that ...
"Endogenous versus Exogenous DNA Adducts: Their Role in Carcinogenesis, Epidemiology, and Risk Assessment". Toxicological ... Singer, B. (1996). "DNA Damage: Chemistry, Repair, and Mutagenic Potential". Regulatory Toxicology and Pharmacology. 23 (1 Pt 1 ...
Ageing Aging brain AP site Direct DNA damage DNA DNA adduct DNA damage theory of aging DNA repair DNA replication Free radical ... estimated that there were 24,000 steady state oxidative DNA adducts per cell in young rats and 66,000 adducts per cell in old ... DNA damage is an alteration in the chemical structure of DNA, such as a break in a strand of DNA, a nucleobase missing from the ... DNA damage is an abnormal chemical structure in DNA, while a mutation is a change in the sequence of base pairs. DNA damages ...
DNA adducts are researched in laboratory settings. A typical experimental design for studying DNA adducts is to induce them ... forming DNA adducts, and inducing double-strand breaks (DSBs). In regards to DNA adduct formation, this analysis was conducted ... Ongoing research on DNA adducts seeks to overcome these complications. It is the hope that in future medical practices DNA ... In molecular genetics, a DNA adduct is a segment of DNA bound to a cancer-causing chemical. This process could lead to the ...
DNA adducts are a form of DNA damage caused by covalent attachment of a chemical moiety to DNA. Adducts that are not removed by ... The HMCES DNA-protein cross-link functions as an intermediate in DNA interstrand cross-link repair New data show that the HMCES ... DNA damage during chromothripsis is caused by deoxyinosine formation on accumulated RNA-DNA hybrids in micronuclei that are ... Repair of topoisomerase 1 (TOP1) DNA protein crosslinks (DPC) limits the efficacy of the TOP1 inhibitor irinotecan in cancer ...
"DNA Adducts" by people in Harvard Catalyst Profiles by year, and whether "DNA Adducts" was a major or minor topic of these ... Ultraviolet A light induces DNA damage and estrogen-DNA adducts in Fuchs endothelial corneal dystrophy causing females to be ... Drug-DNA adducts as biomarkers for metabolic activation of the nitro-aromatic nitrogen mustard prodrug PR-104A. Biochem ... "DNA Adducts" is a descriptor in the National Library of Medicines controlled vocabulary thesaurus, MeSH (Medical Subject ...
... the types and abundances of NA-DNA adducts in circulating leukocytes will at least partly reflect adduct formation in the lung ... The objective of this study is to identify and quantify NA-DNA adducts in mouse lung as well as mouse and human blood to enable ... In Aim 1, I will Identify and quantitate NA-DNA adducts formed in wild-type (WT) mice following NA inhalation exposure, with ... This project will provide direct evidence for the formation of NA-DNA adducts in vivo, lay the foundation for future studies of ...
2. Correlation between DNA adduct formation and biological effect. Most chemicals induce more than one type of DNA adduct. The ... adducts in specific DNA sequences. There is evidence that the distribution of DNA adducts over the genome immediately after ... and characterization of monoclonal antibodies against DNA containing specific DNA adducts or against a purified DNA adduct ... determination of DNA adducts in the same gene to be used for mutation analysis will allow a direct correlation between DNA ...
Sequence- and Region-Specificity of Oxaliplatin Adducts in Naked and Cellular DNA. Jan M. Woynarowski, William G. Chapman, ... Sequence- and Region-Specificity of Oxaliplatin Adducts in Naked and Cellular DNA. Jan M. Woynarowski, William G. Chapman, ... Sequence- and Region-Specificity of Oxaliplatin Adducts in Naked and Cellular DNA. Jan M. Woynarowski, William G. Chapman, ... Sequence- and Region-Specificity of Oxaliplatin Adducts in Naked and Cellular DNA ...
Our preliminary results show that analysis of DNA adducts following ex vivo drug treatment is a feasible approach towards a ... DNA adducts. Measurement of these adducts prior to therapy could be of value to improve cisplatin based cancer therapy. ... Conclusion: Our preliminary results show that analysis of DNA adducts following ex vivo drug treatment is a feasible approach ... The potential of plantinum-DNA adduct determination in ex vivo treated tumor fragments for the prediction of sensitivity to ...
DNA interaction. Comparative DNA binding experiments indicate that 57% of 2 and 33% of 3 were converted into DNA adducts, ... 15, 187-197]. The majority of DNA adducts with 3 are those from the trans- or cis-opening of the epoxide at C5a by the ... indicating the importance of the secondary structure of DNA for both adduct formation and chemical selectivity. The T-shape ... The structures of nine DNA adducts and two racemic tetraols derived from 3 have been determined spectroscopically. Similar ...
Dibenzo[a,l]pyrene induced DNA adduct formation in lung tissue in vivo. Title. Dibenzo[a,l]pyrene induced DNA adduct formation ... Dibenzo[a,l]pyrene induced DNA adduct formation in lung tissue in vivo ...
Bao Y, Bacon J, Williamson G. Effect of phytochemicals on phIP-DNA adduct formation in human HepG2 cells and hepatocytes. In ... Effect of phytochemicals on phIP-DNA adduct formation in human HepG2 cells and hepatocytes. / Bao, Y; Bacon, J; Williamson, G. ... Bao, Y ; Bacon, J ; Williamson, G. / Effect of phytochemicals on phIP-DNA adduct formation in human HepG2 cells and hepatocytes ... Bao, Y., Bacon, J., & Williamson, G. (2001). Effect of phytochemicals on phIP-DNA adduct formation in human HepG2 cells and ...
Reduction in tamoxifen-induced CYP3A2 expression and DNA adducts using antisense technology. Title. Reduction in tamoxifen- ... Reduction in tamoxifen-induced CYP3A2 expression and DNA adducts using antisense technology ...
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DNA adducts have been detected at low levels in human endometrium, and there is much interest in determining whether DNA damage ... DNA adducts have been detected at low levels in human endometrium, and there is much interest in determining whether DNA damage ... DNA adducts have been detected at low levels in human endometrium, and there is much interest in determining whether DNA damage ... DNA adducts have been detected at low levels in human endometrium, and there is much interest in determining whether DNA damage ...
DNA adducts and AHH activity were determined by the 32P-postlabelling technique and the fluorometric method, respectively. The ... DNA adducts and AHH activity were determined by the 32P-postlabelling technique and the fluorometric method, respectively. The ... DNA adducts and AHH activity were determined by the 32P-postlabelling technique and the fluorometric method, respectively. The ... DNA adducts and AHH activity were determined by the 32P-postlabelling technique and the fluorometric method, respectively. The ...
Dibenzo[a,l]pyrene induced DNA adduct formation in lung tissue in vivo. Title. Dibenzo[a,l]pyrene induced DNA adduct formation ... Dibenzo[a,l]pyrene induced DNA adduct formation in lung tissue in vivo ...
Leukocyte DNA adducts were analyzed blindly using 32P postlabeling technique. Adducts were associated with the subsequent risk ... Besides, the association of DNA adduct levels with O 3 indicates a possible role for photochemical smog in determining DNA ... DNA adducts were measured in a case-control study nested in the European Prospective Investigation into Cancer and Nutrition ( ... Our prospective study suggests that leukocyte DNA adducts may predict lung cancer risk of never-smokers. ...
title = "Solution Conformation of the (-)-trans-anti-Benzo[c]phenanthrene-dA ([BPh]dA) Adduct opposite dT in a DNA Duplex: ... Solution Conformation of the (-)-trans-anti-Benzo[c]phenanthrene-dA ([BPh]dA) Adduct opposite dT in a DNA Duplex: Intercalation ... Solution Conformation of the (-)-trans-anti-Benzo[c]phenanthrene-dA ([BPh]dA) Adduct opposite dT in a DNA Duplex: Intercalation ... Solution Conformation of the (-)-trans-anti-Benzo[c]phenanthrene-dA ([BPh]dA) Adduct opposite dT in a DNA Duplex: Intercalation ...
Modulation of novel DNA adducts during human uterine cervix cancer progression. Srivani Ravoori, Manicka V. Vadhanam, Diane D. ... Dive into the research topics of Modulation of novel DNA adducts during human uterine cervix cancer progression. Together ...
... and DNA in vitro. The chemical structures of the DNA adducts were confirmed by accurate mass values, collision-induced ... and DNA in vitro. The chemical structures of the DNA adducts were confirmed by accurate mass values, collision-induced ... and DNA in vitro. The chemical structures of the DNA adducts were confirmed by accurate mass values, collision-induced ... and DNA in vitro. The chemical structures of the DNA adducts were confirmed by accurate mass values, collision-induced ...
Ultimately, the complex problem of the role of the protein or enzyme environment in PAH-DNA adduct conformation and function ... Ultimately, the complex problem of the role of the protein or enzyme environment in PAH-DNA adduct conformation and function ... Ultimately, the complex problem of the role of the protein or enzyme environment in PAH-DNA adduct conformation and function ... Ultimately, the complex problem of the role of the protein or enzyme environment in PAH-DNA adduct conformation and function ...
DNA adduct. fibroblast/human. 100 Āµmol/L. CRNGDP 12,1483,1991. DNA adduct. lymphocyte/mammal (species unspecified). 58 gm/L/3H ... DNA adduct. /Escherichia coli. 286 nmol/L. ARTODN 46,277,1980. ... DNA Damage. other cell types/rat. 30 mmol/L. ARTODN 58,67,1985 ... DNA inhibition. intraperitoneal/rat. 500 Āµg/kg. BICMBE 53,243,1971. DNA inhibition. lymphocyte/mammal (species unspecified). 80 ... DNA Damage. other cell types/human. 30 Āµmol/L. CNREA8 48,1717,1988. ...
Methods: We investigated levels of N 2-ethylidene-dGuo, the major DNA adduct of acetaldehyde, in DNA from human oral cells at ... Methods: We investigated levels of N 2-ethylidene-dGuo, the major DNA adduct of acetaldehyde, in DNA from human oral cells at ... Methods: We investigated levels of N 2-ethylidene-dGuo, the major DNA adduct of acetaldehyde, in DNA from human oral cells at ... Methods: We investigated levels of N 2-ethylidene-dGuo, the major DNA adduct of acetaldehyde, in DNA from human oral cells at ...
I. Polycyclic aromatic hydrocarbon DNA adducts. Cancer Epidemiol Biomarkers Prev. 2002 Aug. 11(8):677-85. [Medline]. ...
... among which two dA and three dG adducts were detected in reactions of AA IVa with calf thymus DNA (CT DNA). However, no DNA ... Ɓcidos AristolĆ³quicos/toxicidade Adutos de DNA/efeitos dos fĆ”rmacos Dano ao DNA/efeitos dos fĆ”rmacos DNA/efeitos dos fĆ”rmacos ... Aristolochic acid IVa forms DNA adducts in vitro but is non-genotoxic in vivo.. Wan, Jingjing; Chen, Ruixue; Yang, Zhou; Xi, ... The competitive reaction of AA I and AA IVa with CT DNA, with adducts levels varying with pH of reaction revealed that AA IVa ...
The adduct levels in DNA were 9630 (dGI), 240 (dCI), 83 (dAI), 6 (dAII), and 28 (TI) pmol/mg DNA, respectively. The preferred ... Identification of adducts derived from reactions of (1-chloroethenyl)oxirane with nucleosides and calf thymus DNA. Lookup NU ... and calf thymus DNA have been studied in aqueous buffered solutions. The adducts from the nucleosides were isolated by reversed ... oxirane with calf thymus DNA gave all of the adducts observed from the individual nucleosides except dGII and dGIII. However, ...
One major adduct and seven minor adducts were formed from each dihy-drodiol-epoxide. The major adduct was, in each case, ... One major adduct and seven minor adducts were formed from each dihy-drodiol-epoxide. The major adduct was, in each case, ... One major adduct and seven minor adducts were formed from each dihy-drodiol-epoxide. The major adduct was, in each case, ... One major adduct and seven minor adducts were formed from each dihy-drodiol-epoxide. The major adduct was, in each case, ...
Recent technological developments have facilitated the identification of multiple DNA adducts in a single experiment. Only a ... A comprehensive understanding of DNA adducts, one of the most plausible origins of cancer mutations, is still elusive, ... chemically reactive substances bind to DNA and form DNA adducts. Certain DNA adducts may impede accurate DNA replication and ... Quantities of DNA adducts in tumor and nontumor sites. Box plots of the molar ratio of DNA adducts in tumor or nontumor sites ...
  • One major adduct and seven minor adducts were formed from each dihy-drodiol-epoxide. (psu.edu)
  • Four major and at least three minor adducts formed with DNA in vitro, which were further analyzed for their base-selectivity. (epa.gov)
  • A tendency of positive correlation was found between DNA adduct levels and AHH inducibility for the all subjects (n=42, r=0.25, p=0.11). (elsevierpure.com)
  • An inverse, statistically significant, association has been found between DNA adduct levels and dietary fibre intake (P = 0Ā·02), vitamin E (P = 0Ā·04) and alcohol (P = 0Ā·03) but not with other nutrients or food groups. (repositoriosalud.es)
  • These positions are of interest to researchers studying DNA adduct formation. (wikipedia.org)
  • DNA adducts have been detected at low levels in human endometrium, and there is much interest in determining whether DNA damage plays a role in tamoxifen-induced endometrial carcinogenesis. (mssm.edu)
  • Thus, HOCl-induced 8-Cl-dG adduct may be involved in inflammation-driven carcinogenesis. (elsevierpure.com)
  • 2015. Cytochrome P450 1b1 in polycyclic aromatic hydrocarbon (PAH)-induced skin carcinogenesis: Tumorigenicity of individual PAHs and coal-tar extract, DNA adduction and expression of select genes in the Cyp1b1 knockout mouse. . (oregonstate.edu)
  • Our preliminary results show that analysis of DNA adducts following ex vivo drug treatment is a feasible approach towards a predictive assay, which warrants further investigation. (nih.gov)
  • In the present study, electrospray ionization coupled with ion trap mass spectrometry (ITMS), triple quadrupole MS or quadrupole time-of-flight MS was applied for the analysis of DNA adducts formed by BBQs. (edu.hk)
  • DNA adducts in scientific experiments are used as biomarkers of exposure. (wikipedia.org)
  • This allows for DNA adducts to serve as biomarkers of exposure to carcinogens from the environment. (wikipedia.org)
  • Drug-DNA adducts as biomarkers for metabolic activation of the nitro-aromatic nitrogen mustard prodrug PR-104A. (harvard.edu)
  • Acetaldehyde, the major metabolite of ethanol, reacts with DNA to produce adducts, which are critical in the carcinogenic process and can serve as biomarkers of exposure and, possibly, of disease risk. (umn.edu)
  • Both types of adducts are biomarkers of carcinogen exposure and possibly of cancer risk, and were measured, respectively, in leucocytes and erythrocytes of 1086 (DNA adducts) and 190 (Hb adducts) non-smokers. (repositoriosalud.es)
  • Owing for the large toxicity of regular HIV-2 manufacturer anticancer drugs, precision in treatment holds excellent significance to decrease toxic sideeffects and increase efficacy, and this is accomplished by designing drug-based biomarkers (Drug-DNA biomarkers), which could yield appropriateness of drug to which patient may respond [16]. (lrrk2inhibitor.com)
  • designing such biomarkers requires adductomics, which identify and quantify adducts formed on account of anticancer drugs. (lrrk2inhibitor.com)
  • This good correlation witnessed in the majority in the studies demonstrates the high prospective of DNA adductomics in designing drug biomarkers to evaluate the susceptibility in the patient to a specific anticancer drug and offers an chance to markedly shift from a single size fits for all approach to patient-oriented method, customized treatment and precision therapy (Figure three) [15].Int. J. Mol. (lrrk2inhibitor.com)
  • Aristolochic acid IVa forms DNA adducts in vitro but is non-genotoxic in vivo. (bvsalud.org)
  • Adducts derived from either dGp, poly dG-dC, or poly dG comigrated with the DNA adducts in 3 solvent systems indicating that CPP-3,4-epoxide forms DNA adducts almost exclusively with deoxyguanosine. (epa.gov)
  • Ultraviolet A light induces DNA damage and estrogen-DNA adducts in Fuchs endothelial corneal dystrophy causing females to be more affected. (harvard.edu)
  • Loss of NQO1 generates genotoxic estrogen-DNA adducts in Fuchs Endothelial Corneal Dystrophy. (harvard.edu)
  • Estrogen metabolism and formation of estrogen-DNA adducts in estradiol-treated MCF-10F cells. (nebraska.edu)
  • Dive into the research topics of 'Estrogen metabolism and formation of estrogen-DNA adducts in estradiol-treated MCF-10F cells. (nebraska.edu)
  • The presence of such an adduct indicates prior exposure to a potential carcinogen, but it does not necessarily indicate the presence of cancer in the subject animal. (wikipedia.org)
  • In the direct case, a carcinogen can bind to DNA and cause it to distort or become cross-linked. (wikipedia.org)
  • dT linter duplex has been determined by incorporating intramolecular and carcinogen-DNA proton-proton distances defined by lower and upper bounds deduced from NOESY data sets as restraints in molecular mechanics computations in torsion angle space. (psu.edu)
  • These stereochemically induced structural differences between isomeric [BPh]dA lesions derived from the binding of chiral (+)- and (-)-anti-BPhDE enantiomers may in turn profoundly influence the interactions of the carcinogen-modified DNA with repair and replication enzymes in the cell. (psu.edu)
  • Impact: Our results provide some of the first conclusive evidence linking exposure to a lifestyle carcinogen and kinetics of DNA adduct formation in humans. (umn.edu)
  • Bulky carcinogen-DNA adducts commonly cause replicative polymerases to stall, leading to a switch to bypass polymerases. (nyu.edu)
  • The study demonstrated 2-monobromobenzoquinone and 2,6-dibromobenzoquinone could covalently bind to deoxyguanosine (dG) and DNA in vitro. (edu.hk)
  • The reactions of (1-chloroethenyl)oxirane with 2ā€²-deoxyguanosine, 2ā€²-deoxyadenosine, 2ā€²-deoxycytidine, thymidine, and calf thymus DNA have been studied in aqueous buffered solutions. (ncl.ac.uk)
  • AA IVa reacted with 2'-deoxyadenosine (dA) and 2'- deoxyguanosine (dG) to form three dA and five dG adducts as identified by high-resolution mass spectrometry , among which two dA and three dG adducts were detected in reactions of AA IVa with calf thymus DNA (CT DNA ). (bvsalud.org)
  • The major adduct was, in each case, characterized by its pH-dependent partition coefficient, stability to base, mass spectrum, ultraviolet spectrum, and nuclear magnetic resonance spectrum as a deoxyguanosine derivative resulting from addition of the exocydic amino group of deoxyguanosine to the benzyiic carbon of the epoxide ring of the dihydrodiol-epoxide. (psu.edu)
  • One of the consequences caused by both substances is an oxidative DNA damage and DNA adducts 8-hydroxy-2'-deoxyguanosine (8-OHdG) production as a biomarker of cancer risk. (ui.ac.id)
  • 8-Chloro-2ā€²-deoxyguanosine (8-Cl-dG) is a major DNA adduct formed by HOCl and has been detected from the liver DNA and urine of rats administered lipopolysaccharide in an inflammation model. (elsevierpure.com)
  • In brief, although it could form DNA adducts in vitro , AA IVa was non-genotoxic in vivo, which was attributed to its low reactivity and biotransformation into an easily excreted metabolite rather than bioactivation. (bvsalud.org)
  • Both DE-I and DE-II were individually reacted with calf thymus DNA in vitro. (psu.edu)
  • 2-Nitrotoluene was genotoxic in a range of in vitro and in vivo assays, was notably clastogenic in human peripheral lymphocytes and formed DNA adducts in exposed rodents. (gc.ca)
  • Reactive quinone and epoxide metabolites of similar compounds, such as benzo[a]pyrene, have been shown to enact their carcinogenecity through DNA adduct formation. (nih.gov)
  • Reaction of Cyclopent(c,d)pyrene-3,4-epoxide with DNA and Deoxynucleotides. (epa.gov)
  • The DNA was enzymatically hydrolyzed to deoxyribonudeosides, and the modified deoxyribonudeosides were separated by chromatography on Sephadex LH-20 and analyzed by high-performance liquid chromatography. (psu.edu)
  • Adduct formation is determined by the structures of reactive chemicals, the movement(s) of electrophiles, and the capacity of the compounds to bind with DNA, potentially driving adduct formation to specific nucleophilic sites. (wikipedia.org)
  • New data show that the HMCES protein suppresses DNA double-strand break formation by cross-linking to and thereby stabilizing an abasic site generated during replication-coupled repair of a DNA interstrand cross-link, thus demonstrating a physiological role of HMCES in DNA repair. (nature.com)
  • DNA damage during chromothripsis is caused by deoxyinosine formation on accumulated RNA-DNA hybrids in micronuclei that are then recognized by N -methyl-purine DNA glycosylase and cleaved by apurinic/apyrimidinic endonuclease. (nature.com)
  • 1. Investigations concerning the correlation between exposure to chemicals and formation of DNA adducts. (europa.eu)
  • 2. Correlation between DNA adduct formation and biological effect. (europa.eu)
  • Response to cisplatin-therapy is assumed to be related to the formation of platinum (Pt)-DNA adducts. (nih.gov)
  • The overall dA/dG ratios were lower with denatured DNA, indicating the importance of the secondary structure of DNA for both adduct formation and chemical selectivity. (uri.edu)
  • Bao, Y , Bacon, J & Williamson, G 2001, Effect of phytochemicals on phIP-DNA adduct formation in human HepG2 cells and hepatocytes . (uea.ac.uk)
  • We have previously developed the technology to quantify acetaldehyde-DNA adducts in human tissues, but there are no studies in the literature defining the formation and removal of acetaldehyde-DNA adducts in people who consumed alcohol. (umn.edu)
  • Conclusion: These results show an effect of alcohol on oral cell DNA adduct formation, strongly supporting the key role of acetaldehyde in head and neck cancer caused by alcohol drinking. (umn.edu)
  • Aristolochic acids (AAs) are a family of natural compounds with AA I and AA II being known carcinogens , whose bioactivation causes DNA adducts formation. (bvsalud.org)
  • The initial events responsible for these carcinogenic and irreversible mutations involve DNA adduct formation, which is the focus of this paper. (biomedcentral.com)
  • Formation of estrogen metabolites that react with DNA is thought to be a mechanism of cancer initiation by estrogens. (nebraska.edu)
  • Inclusion of Ro41-0960 and E 2 in the medium blocked formation of methoxy CE, and depurinating adducts were observed. (nebraska.edu)
  • We conclude that low COMT activity and increased formation of depurinating adducts can be critical factors leading to initiation of breast cancer. (nebraska.edu)
  • Fibres could reduce the formation of DNA adducts in different manners, by diluting potential food mutagens and carcinogens in the gastrointestinal tract, by speeding their transit through the colon and by binding carcinogenic substances. (repositoriosalud.es)
  • In this study we examined the time course and interindividual variation of 1-hydroxypyrene-glucuronide (1-OHP-gluc) excretion in urine and PAH-DNA adduct formation in peripheral white blood cells (WBCs) after charbroiled (CB) beef consumption. (johnshopkins.edu)
  • ole in BaP metabolism at the same time as DNA adduct formation. (lrrk2inhibitor.com)
  • Secondly, patients might be injected with micro doses of DNA alkylating drugs and look for adduct formation in tumor tissue biopsy and peripheral blood mononuclear cells (PBMC). (lrrk2inhibitor.com)
  • We determined Pt-GG and Pt-AG adduct levels by use of 32P-postlabeling after ex vivo cisplatin treatment of fragments of head and neck squamous cell carcinoma (HNSCC) xenografts (five lines), and of tumor biopsies from patients with HNSCC (n = 8) and testicular cancer (n = 8). (nih.gov)
  • When patient tumor fragments were exposed ex vivo to 80 microM cisplatin for one hour, adduct levels were similar in HNSCC and testicular cancer. (nih.gov)
  • Finally, cancer cell and regular cells are exposed to DNA modifying agent's ex vivo to determine if there's any adducts are formed. (lrrk2inhibitor.com)
  • These findings establish a mechanism for co-targeting DNA damage-induced cell cycle checkpoints in combination with repair of cisplatin-DNA lesions in vivo using RNAi nanocarriers, and motivate further exploration of ASL as a generalized strategy to improve cancer treatment. (nature.com)
  • We have investigated the correlation between DNA adduct levels and aryl hydrocarbon hydroxylase (AHH) activity in peripheral lymphocyte samples obtained from 42 lung cancer patients. (elsevierpure.com)
  • There was no statistically significant correlation between DNA adduct levels and non-induced or MC- induced AHH activity. (elsevierpure.com)
  • In addition, similar correlation of DNA adducts with AHH inducibility was also observed in the GSTM1 present genotype (n = 17, r = 0.44, p = 0.07) and GSTP1-AA genotype (n = 29, r = 0.37, p = 0.05) individuals. (elsevierpure.com)
  • After multivariate regression analysis these inverse correlations remained statistically significant, except for the correlation adducts v. fruit intake. (repositoriosalud.es)
  • To further potentiate above outcomes, similarly there was positive correlation was observed in preclinical and clinical information for Drug induced DNA adduct and physiological response. (lrrk2inhibitor.com)
  • The correlation coefficients between DNA adduct levels and styrene exposure, albumin adduct levels and SO exposure, and SCEs and SO exposure were higher among nonsmokers than among smokers. (cdc.gov)
  • In general, lower percentages were observed with denatured calf-thymus DNA. (uri.edu)
  • As for base selectivity, 2 showed a greater affinity for dA relative to dG (dA/dG ratio, 0.79) than 3 (0.56) when reacted with native calf-thymus DNA. (uri.edu)
  • Reaction of (1-chloroethenyl)oxirane with calf thymus DNA gave all of the adducts observed from the individual nucleosides except dGII and dGIII. (ncl.ac.uk)
  • Characterization of DNA adducts derived from syn-benzo[ghi]fluoranthen" by Hui-Fang Chang, Duane M. Huffer et al. (uri.edu)
  • This adduct is derived from the covalent binding of (-)-1,2-dihydroxy-3,4-epoxy-l, 2,3,4-tetrahydro-benzo[c]phenanthrene [(-)-anti-BPhDE] to N6 of dA6 in this duplex sequence. (psu.edu)
  • The N3 and N7 locations (nucleotide positioning) of guanine and adenine are believed to be the most nucleophilic, and hence, they form adducts selectively over exocyclic oxygen atoms. (wikipedia.org)
  • Adducted plasmids were transfected into nucleotide excision repair proficient (GM00637) or deficient (GM04429, XPA) human fibroblasts. (mssm.edu)
  • We have investigated nucleotide incorporation opposite the major adduct of 2-amino-1-methyl-6- phenylimidazo[4,5-b]pyridine (PhIP) in the DinB family polymerase, Dpo4, using molecular modeling and molecular dynamics (MD) simulations. (nyu.edu)
  • vii) Further development of post-labelling methods for other than bulky DNA adducts. (europa.eu)
  • Three basic types of conformers have been discovered for PAH-DNA adducts (Table 4, Figures 11, 12, and 18): (1) minor groove external binding sites, (2) base-displaced intercalative structures, and (3) intercalative insertions of the bulky PAH residues into the helix without base displacement (modified classical intercalation). (nyu.edu)
  • Versatility of Y-family Sulfolobus solfataricus DNA polymerase Dpo4 in translesion synthesis past bulky N2-alkylguanine adducts. (neb.com)
  • Finally, bulky C8-dG adducts, situated in the major groove, are likely to impede translocation in this polymerase (Rechkoblit et al. (nyu.edu)
  • ii) Development of HPLC separation systems using an electrochemical detector, which would allow the detection of certain unlabelled adducts. (europa.eu)
  • The adducts from the nucleosides were isolated by reversed-phase HPLC, and characterized by their UV absorbance and 1H and 13C NMR spectroscopic and mass spectrometric features. (ncl.ac.uk)
  • Estrogen metabolites and depurinating DNA adducts in culture medium were analyzed by HPLC with electrochemical detection. (nebraska.edu)
  • The 8-OHdG DNA adducts was analyzed using a reverse phase HPLC chromatography with UV/vis detector at the wavelength of 254 nm. (ui.ac.id)
  • Carcinogens are chemical or physical agents that cause DNA damage, which may later develop into cancer. (wikipedia.org)
  • Exposure to them can directly or indirectly cause DNA damage. (wikipedia.org)
  • Many compounds require enzyme metabolic activation to become mutagenic and cause DNA damage. (wikipedia.org)
  • ROS and RNS are known to cause DNA damage via oxidative processes. (wikipedia.org)
  • Research has indicated that many different chemicals may change human DNA and that lifestyle and host characteristics can impact the extent of DNA damage. (wikipedia.org)
  • Humans are constantly exposed to a diverse combination of potentially dangerous substances that might cause DNA damage. (wikipedia.org)
  • DNA adducts are a form of DNA damage caused by covalent attachment of a chemical moiety to DNA. (nature.com)
  • Protective effects of Alda-1, an ALDH2 activator, on alcohol-derived DNA damage in the esophagus of human ALDH2*2 (Glu504Lys) knock-in mice. (harvard.edu)
  • A series of model compounds which include methylating and ethylating agents were used to determine the nature and the frequency of different types of deoxyribonucleic acid (DNA) damage caused by the chemicals. (europa.eu)
  • Parallel to the measurements of DNA damage the frequency of mutations was determined in different organisms which include cultured mammalian cells, mouse germ cells, Drosophila, yeast, Escherichia coli and Salmonella typhimurium. (europa.eu)
  • Furthermore, removal of certain type of DNA damage from actively transcribed genes is likely to be faster than from the genome overall. (europa.eu)
  • Differential damage and repair of DNA-adducts induced by anti-cancer drug cisplatin across mouse organs. (unc.edu)
  • Cisplatin interacts with DNA mainly in the form of Pt-d(GpG) di-adduct, which stalls cell proliferation and activates DNA damage response. (unc.edu)
  • We find different DNA damage and repair spectra across mouse organs, which are associated with tissue-specific transcriptomic and epigenomic profiles. (unc.edu)
  • Detecting drug-DNA adducts could also be a predictive biomarker for cancer drug induced DNA harm, to ascertain drug induced DNA damage you can find 3 major exposure approaches are made use of. (lrrk2inhibitor.com)
  • C8-Substituted Imidazotetrazine Analogs Overcome Temozolomide Resistance by Inducing DNA Adducts and DNA Damage FRONTIERS IN ONCOLOGY. (nottingham.ac.uk)
  • In response to DNA damage, a synthetic lethal relationship exists between the cell cycle checkpoint kinase MK2 and the tumor suppressor p53. (nature.com)
  • Therefore, compared to normal p53-proficient cells, p53-defective cells are more reliant on MK2 activity, which drives an alternative cell cycle checkpoint pathway that stabilizes the CKI inhibitors p27 Kip1 and Gadd45Ī± in order to maintain G 1 /S and G 2 /M arrest after certain types of DNA damage 16 , 18 . (nature.com)
  • There is evidence that the distribution of DNA adducts over the genome immediately after exposure is not random, but that certain DNA sequences are damaged to a higher extent. (europa.eu)
  • iii) Isolation and characterization of monoclonal antibodies against DNA containing specific DNA adducts or against a purified DNA adduct itself. (europa.eu)
  • Similar characterization of adducts obtained from the anti-isomer 2 was described in the preceding paper in this issue [Chang et al. (uri.edu)
  • the miscoding frequency and specificity varies depending on the DNA polymerase used. (elsevierpure.com)
  • The results to date include that measurements of DNA adduct frequencies can give information concerning the mutagenic potency of a genotoxic agent, but these determinations should be accompanied by measurements of the effects of DNA repair mechanisms on the persistence of the DNA lesions. (europa.eu)
  • The mutagenic properties of each of these type of adducts can vary significantly. (europa.eu)
  • Adducts that are not removed by the cell can cause mutations that may give rise to cancer. (nature.com)
  • Relative mutation frequencies increased with the adduct level, with 1.3-3.6-fold higher numbers of mutations in the XP cells compared to the GM00637 cells, indicating that NER plays a significant role in the removal of these particular tamoxifen DNA adducts. (mssm.edu)
  • In both cell lines, as the adduct level increased, the proportion of GC ā†’ AT transitions decreased and GC ā†’ TA transversions, mutations known to arise from the major tamoxifen adducts, increased. (mssm.edu)
  • A comprehensive understanding of DNA adducts, one of the most plausible origins of cancer mutations, is still elusive, especially in human tissues in clinical settings. (biomedcentral.com)
  • Certain DNA adducts may impede accurate DNA replication and generate mispairing which contribute to DNA mutations [ 12 ]. (biomedcentral.com)
  • Measurement of these adducts prior to therapy could be of value to improve cisplatin based cancer therapy. (nih.gov)
  • The adduct levels in the samples of two HNSCC patients who received cisplatin chemotherapy were in line with the hypothesis that higher adduct levels are associated with a better response. (nih.gov)
  • On the cisplatin-DNA adduct along with the expression and activity of p-glycoprotein. (itkinhibitor.com)
  • A. Effects of WYC02 and WYC0209 on cisplatin-DNA adduct. (itkinhibitor.com)
  • The percentage of cisplatin-DNA adduct good cells have been measured by flow cytometry and are represented as mean EM of three replications. (itkinhibitor.com)
  • Since inhibition of ATR seems to sensitize tumors to cisplatin-induced cell death [15], the elevated cisplatinDNA adducts evident right here might be either an indirectFigure five: Knockdown of Atr or p-glycoprotein with sirNA boost the cisplatin-DNA adduct in 5637 cells. (itkinhibitor.com)
  • Effects of siATR knockdown on A. cisplatin-DNA adduct and b. (itkinhibitor.com)
  • We show that loss of the DNA repair protein XPA markedly augments the synthetic lethality between MK2 and p53, enhancing anti-tumor responses alone and in combination with cisplatin chemotherapy. (nature.com)
  • A typical experimental design for studying DNA adducts is to induce them with known carcinogens. (wikipedia.org)
  • The presence of endogenous carcinogens contributes to levels of DNA adducts in a patient. (wikipedia.org)
  • From 59 subjects who had received gastrectomy for gastric cancer, 306 samples of nontumor tissues and 15 samples of tumors (14 cases) were taken for DNA adductome analysis. (biomedcentral.com)
  • The concept has now been extended to embrace synthetic lethal drug sensitivity, such as that observed with PARP inhibitors in combination with DNA-damaging chemotherapy in a variety of BRCA defective tumors 10 . (nature.com)
  • The NMR structural studies have elucidated a variety of strikingly diverse conformational themes among adducts of polycyclic aromatic compounds with DNA. (nyu.edu)
  • Remarkably, this theme of opposite orientations persists regardless of (1) the conformer type (minor groove, base-displaced/intercalation, classical intercalation), or (2) the nature of the polycyclic aromatic parent compound (5-MeC, BPh, BP, Ī±-[SO]) and adduct site (guanine or adenine group, see Table 4). (nyu.edu)
  • The conformational theme of base-displaced intercalation, observed in the cases of the cis- anti-[BP]N 2 -dG adducts, is also found for adducts derived from polycyclic aromatic amines. (nyu.edu)
  • We hypothesize that such equilibria may prevail in other adducts derived from polycyclic aromatic hydrocarbons and amines, as well. (nyu.edu)
  • An additional conformational motif, a major groove adduct structure in the case of Ī±-(N 6 -adenyl)styrene oxide adducts, has been observed (Table 4). (nyu.edu)
  • Generally, the reaction mechanism for the DNA adduction involved Michael addition between the electron-deficient carbon from the quinone and the nucleophilic exocyclic nitrogen from the dG followed by reductive cyclization with loss of a small molecule such as H 2 O, or HBrO. (edu.hk)
  • It was of particular interest to note that some adducts were generated from the reaction of one dG molecule with two BBQ molecules. (edu.hk)
  • The reaction of 2ā€²deoxyadenosine with (1-chloroethenyl)oxirane gave two adducts: N1-(3-chloro-2-hydroxy-3-buten-1-yl)-2ā€²-deoxyadenosine (dAI) and N6-(3-chloro-2-hydroxy-3-buten-1-yl)-2ā€²-deoxyadenosine (dAII). (ncl.ac.uk)
  • The competitive reaction of AA I and AA IVa with CT DNA , with adducts levels varying with pH of reaction revealed that AA IVa was significantly less reactive than AA I, probably by hydroxyl deprotonation of AA IVa, which was explained by theoretical calculations for reaction barriers, energy levels of the molecular orbits , and charges at the reaction sites. (bvsalud.org)
  • These findings suggest that DNA adduct levels are mediated by CYP1A1 enzyme, and AHH inducibility may be a more relevant indicator than specific AHH activity for explaining the variation of DNA adduct levels in lymphocytes. (elsevierpure.com)
  • pSP189 plasrnid DNA containing the supF gene was treated with Ī±-acetoxytamoxifen and adduct levels (0.5-8.0 adducts per plasmid) determined by 32 P-postlabeling. (mssm.edu)
  • Methods: We investigated levels of N 2 -ethylidene-dGuo, the major DNA adduct of acetaldehyde, in DNA from human oral cells at several time points after consumption of increasing alcohol doses. (umn.edu)
  • This study investigated the effect of inhibiting COMT activity on the levels of depurinating 4-OHE 1 (E 2 )-1-N3Ade and 4-OHE 1 (E 2 )-1-N7Gua adducts in human breast epithelial cells. (nebraska.edu)
  • Firstly, upon very first therapy with chemotherapeutic agents in individuals, analysis for detecting adducts in different biological samples like circulating tumor cells, tumor tissue biopsy and other tissues at therapeutic levels of chemotherapy. (lrrk2inhibitor.com)
  • Mean albumin adduct levels ranged from 0.286 nanomoles per gram (nmol/g) of albumin to 1.68nmol/g. (cdc.gov)
  • Mean DNA adduct levels were significantly higher among smokers than among nonsmokers. (cdc.gov)
  • Due to internal or external factors, chemically reactive substances bind to DNA and form DNA adducts. (biomedcentral.com)
  • The alternation of the genome caused by covalent binding of chemicals or their metabolites to DNA provides a viable mechanism for carcinogenicity. (edu.hk)
  • The estrogens estrone (E 1 ) and estradiol (E 2 ) can form catechol estrogen (CE) metabolites, catechol estrogen quinones [E 1 (E 2 )-3,4-Q], which react with DNA to form predominantly depurinating adducts. (nebraska.edu)
  • The chemical structures of the DNA adducts were confirmed by accurate mass values, collision-induced fragmentation tandem mass spectra as well as isotopic patterns. (edu.hk)
  • A similar spectra of adducts was exhibited by dGp, poly dG-dC and poly dG. (epa.gov)
  • Liquid chromatography-mass spectrometry (LC-MS): Liquid chromatography-mass spectrometry is useful in testing DNA adducts, but does have a different approach than a 32P-postlabeling assay. (wikipedia.org)
  • Enzyme linked immunosorbent assay (ELISA): ELISA contains an antigen in solution that can bind with DNA adducts. (wikipedia.org)
  • To this end several assay systems were first developed to measure DNA adduct frequencies. (europa.eu)
  • vi) Development of a sensitive assay for the measurement of apurinic sites in DNA. (europa.eu)
  • However, no DNA adducts were detected in the kidney , liver , and forestomach of orally dosed mice at 40 mg/kg/day for 2 days, and bone marrow micronucleus assay also yielded negative results . (bvsalud.org)
  • PAH-DNA adducts were measured in WBCs by enzyme-linked immunosorbent assay (ELISA) in order to assess macromolecular dose. (johnshopkins.edu)
  • The diolepoxides 2 and 3 are rigid structure analogues of anti- and syn-BcPDE (5 and 6), respectively, thus serving as models for probing molecular deformity and diol conformation in diolepoxide - DNA interaction. (uri.edu)
  • Ultimately, the complex problem of the role of the protein or enzyme environment in PAH-DNA adduct conformation and function will need to be addressed. (nyu.edu)
  • We have investigated in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort the association between dietary items (food groups and nutrients) and aromatic DNA adducts and 4-aminobiphenyl-Hb adducts. (repositoriosalud.es)
  • The present study suggests that fibre intake in the usual range can modify the level of DNA or Hb aromatic adducts, but such role seems to be quantitatively modest. (repositoriosalud.es)
  • Our results show that the dG-C8-PhIP adduct can be accommodated in the spacious major groove Dpo4 open pocket, with Dpo4 capable of incorporating dCTP, dTTP or dATP opposite the adduct reasonably well. (nyu.edu)
  • They can initiate mutagenesis in DNA by interfering with the replication process. (wikipedia.org)
  • Fluorescence labeling: Certain DNA adducts can also be detected by the means of fluorescence because they contain fluorescent chromophores. (wikipedia.org)
  • The human gut bacterial genotoxin colibactin alkylates DNA. (harvard.edu)
  • Only a few attempts toward this "DNA adductome approach" in human tissues have been reported. (biomedcentral.com)
  • Geospatial information on DNA adducts in human organs has been scarce. (biomedcentral.com)
  • Mass spectrometry of human gastric mucosal DNA was performed to identify DNA adducts associated with environmental factors. (biomedcentral.com)
  • We characterized 7 DNA adducts in the nontumor portion of the human stomach in both gastric cancer subjects and nongastric cancer subjects. (biomedcentral.com)
  • A more expansive DNA adductome profile would provide a comprehensive understanding of the origin of human cancer in the future. (biomedcentral.com)
  • In this study, we explored the miscoding properties of the 8-Cl-dG adduct generated by human DNA polymerases (pols). (elsevierpure.com)
  • The overall objective of this Funding Opportunity Announcement (FOA) is to support innovative research on adducts to cellular macromolecules as indicators of exposures to endogenous and exogenous cancer risk factors relevant to exposures in human populations. (nih.gov)
  • Recent technological developments have facilitated the identification of multiple DNA adducts in a single experiment. (biomedcentral.com)
  • Guanine's N7 position is exposed in the major groove of double-helical DNA, making it more suitable for adduction than when compared to adenine's N3 position, which is orientated in the minor groove. (wikipedia.org)
  • This graph shows the total number of publications written about "DNA Adducts" by people in Harvard Catalyst Profiles by year, and whether "DNA Adducts" was a major or minor topic of these publication. (harvard.edu)
  • This study investigates the mutagenicity of tamoxifen DNA adducts formed by Ī±-acetoxytamoxifen, a reactive ester producing the major DNA adduct formed in livers of tamoxifen-treated rats. (mssm.edu)
  • The results of this study show that the major DNA adducts formed from 5-methylchrysene via DEI and DE-II are structurally similar. (psu.edu)
  • Most chemicals induce more than one type of DNA adduct. (europa.eu)
  • Further development of methodologies for the detection and quantification of DNA adducts in the genome overall, which will involve: (i) The use of radioactively labelled model compounds which allow the quantification of labelled DNA adducts at low frequency. (europa.eu)
  • Persistence of adducts was observed for testicular cancer in the additional drug-free period. (nih.gov)
  • The structures of nine DNA adducts and two racemic tetraols derived from 3 have been determined spectroscopically. (uri.edu)
  • Furthermore, reactive intermediates can be produced in the body as a result of oxidative stress, thus harming the DNA. (wikipedia.org)
  • a.Determination of DNA adduct frequencies as a function of time in: Different organs of mice, hamsterand rat, including mouse and rat germ cells. (europa.eu)
  • The opposite orientations relative to the modified bases of chemically identical adduct pairs derived from chiral pairs of diol epoxide stereoisomers are noteworthy. (nyu.edu)
  • These DNA adducts showed considerable correlations with each other. (biomedcentral.com)
  • These interactions typically cause chemical adducts to form in the cell. (wikipedia.org)
  • v) Further development of immuno histochemical methods for the detection of DNA adducts in various organs and cell types of mammals. (europa.eu)
  • Briefly, DNA was extracted from each sample with antioxidants, digested into nucleosides, separated by liquid chromatography, and then electrospray-ionized. (biomedcentral.com)