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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peroxisome proliferators are considered as a novel class of hepatocarcinogenic agents because of their non-mutagenic nature and their ability to cause a significant increase in the levels of hydrogen peroxide generating peroxisomal fatty acid beta-oxidation enzyme system in the liver. Sustained increase in the number of peroxisomes in liver has been shown to induce oxidative stress in the liver. Increased levels of H2O2 generation, hydroxyl free-radical formation, lipid peroxidation and accumulation of lipofuscin are found in the livers of rats following long-term treatment with peroxisome proliferators. Recent evidence indicates the presence of 8-hydroxydeoxyguanosine in the liver DNA of rats chronically treated with a peroxisome proliferator suggesting that this may be the basis for carcinogenesis by this class of non-mutagenic carcinogens.
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PMID:Oxidative DNA damage caused by persistent peroxisome proliferation: its role in hepatocarcinogenesis. 267 2

It has been shown previously that deoxyguanosine residues in DNA are hydroxylated at the C-8 position both in vitro and in vivo to produce 8-hydroxydeoxyguanosine (8-OH-dG) by various agents that produce oxygen radicals such as reducing reagents-O2, metal ions-O2, polyphenol-H2O2-Fe3+, asbestos-H2O2 or ionizing radiation. These agents are mostly either mutagenic or carcinogenic; therefore, the formation of 8-OH-dG can also be considered a likely cause of mutation or carcinogenesis by oxygen radicals. It is of interest to know whether the 8-OH-dG residue in DNA is misread during DNA replication. To answer this question, we have examined the effect of the 8-OH-dG residue in DNA on the fidelity of DNA replication using a DNA synthesis system in vitro with Escherichia coli DNA polymerase I (Klenow fragment). The synthetic oligodeoxynucleotides, with or without an 8-OH-dG residue in a specified position, were chemically synthesized and used as templates for DNA synthesis under the conditions of the dideoxy chain termination sequencing method. Surprisingly, in addition to misreading of the 8-OH-dG residue itself, pyrimidines next to the 8-OH-dG residue (G has not yet been tested) were also misread.
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PMID:Misreading of DNA templates containing 8-hydroxydeoxyguanosine at the modified base and at adjacent residues. 357 69

Following oral administration of a renal carcinogen, potassium bromate (KBrO3), to the rat, a significant increase of 8-hydroxydeoxyguanosine (8-OH-dG) in kidney DNA was observed. In the liver, a non-target tissue, the increase in 8-OH-dG was not significant. The non carcinogenic oxidants, NaCIO and NaCIO2, had no effect on 8-OH-dG formation in kidney DNA. These results suggest that formation of 8-OH-dG in tissue DNA is closely related to KBrO3 carcinogenesis.
Carcinogenesis 1987 Dec
PMID:Oral administration of the renal carcinogen, potassium bromate, specifically produces 8-hydroxydeoxyguanosine in rat target organ DNA. 367 21

Diesel exhaust particles (DEP) cause tumors in the respiratory tracts of experimental animals. It was previously shown that DEP produced superoxide and hydroxyl radical. To examine whether oxygen radicals are involved in mouse lung tumorigenesis induced by DEP, formation of an oxidative DNA damage, 8-hydroxydeoxyguanosine (oh8dG), by DEP was investigated. Furthermore, the role of high dietary fat and beta-carotene on this process was studied. After intratracheal instillation of DEP, a significant increase of oh8dG in mouse lung DNA was observed. High dietary fat enhanced the formation of oh8dG in lung DNA. Intake of beta-carotene suppressed the formation of oh8dG in lung DNA, but the protective effect of beta-carotene against this process was not statistically significant. These results suggest that formation of oh8dG in lung DNA was induced by oxygen free radicals produced by DEP. Thus, it is possible that oh8dG is a promutagenic lesion in DEP-induced lung tumorigenesis in mice and high dietary fat enhances this process through the generation of oh8dG in mouse lung DNA.
Carcinogenesis 1995 Jun
PMID:Formation of an oxidative DNA damage, 8-hydroxydeoxyguanosine, in mouse lung DNA after intratracheal instillation of diesel exhaust particles and effects of high dietary fat and beta-carotene on this process. 754 May 13

Oxygen free radicals cause extensive chemical changes in DNA, including base and sugar modifications and strand breaks. In the present study we found that a mutagen, glyoxal, is produced by exposure of DNA to an oxygen radical forming system (5 mM FeSO4-EDTA, 37 degrees C, 60 min). It was produced with 17 times higher efficiency than 8-hydroxydeoxyguanosine. Thus it is possible that the formation of glyoxal is one of the major types of damage in DNA exposed to oxygen free radicals.
Carcinogenesis 1995 Sep
PMID:Formation of a mutagen, glyoxal, from DNA treated with oxygen free radicals. 755 85

Free radical generation by metabolic redox cycling between catechol estrogens and their quinones and subsequent hydroxyl radical damage to DNA have been proposed to mediate estrogen-induced renal carcinogenesis in the hamster. In this study the content of 8-hydroxy-2'-deoxy-guanosine (8-OHdG), a marker product of hydroxyl radical action, was examined in DNA incubated with a liver microsomal activating system and with catechol estrogens, equilenin-3,4-quinone or with parent estrogens. Equilenin-3,4-quinone increased the formation of 8-OHdG by 50% over control levels. 4-Hydroxyestrone and 4-hydroxy-estradiol raised 8-OHdG contents significantly, to 1.61 +/- 0.79 and 1.27 +/- 0.31 8-OHdG/10(5) deoxyguanosine (dG) respectively over controls (0.68 +/- 0.25 8-OHdG/10(5) dG). The corresponding 2-hydroxylated estrogens and the parent hormones estrone, estradiol and equilenin did not affect 8-hydroxylation of guanine bases of DNA. In incubations of catechol estrogens with microsomes and cumene hydroperoxide the 4-hydroxyestrogens were oxidized to quinones more rapidly than the 2-hydroxyestrogens. Our data support a mechanism of hydroxyl radical generation from estrogens by redox cycling between 4-hydroxylated metabolites and their quinones. The rapid oxidation of 4-hydroxylated estrogens to quinones, their redox cycling and hydroxyl radical damage to DNA is consistent with the previously reported carcinogenic activities of 4-hydroxylated, but not of 2-hydroxylated, catechol estrogens.
Carcinogenesis 1995 Oct
PMID:Microsome-mediated 8-hydroxylation of guanine bases of DNA by steroid estrogens: correlation of DNA damage by free radicals with metabolic activation to quinones. 758 68

7,8-Dihydro-8-oxo-2'-deoxyguanosine (8-oxo-dG) was measured as an indicator of nickel-induced oxidative base damage in the presence of H2O2. Heterochromatic proteins isolated from Chinese hamster liver cells enhanced the formation of 8-oxo-dG induced by NiCl2 and H2O2 in vitro, whereas euchromatic proteins inhibited this reaction. The inhibitory effect of euchromatic proteins on dG oxidation may be due to the oxygen radical scavenging effects of low molecular weight protein-rich fractions. Gel electrophoresis confirmed that histone H1 was present at a higher concentration in heterochromatin than in euchromatin. It is believed that the presence of nickel-protein complexes in cells is crucial for the formation of reactive oxygen species (ROS). We found that Ni2+ binds to histone H1 and core histones as determined by 63Ni autoradiography of proteins on nitrocellulose membranes. In vitro studies showed that commercially purified histone H1, and to a considerably lesser extent core histones, enhanced the NiCl2 and H2O2 catalyzed formation of 8-oxo-dG in a reaction containing free dG base. Since histone H1 is a lysine- and alanine-rich protein, the levels of 8-oxo-dG induced by NiCl2 and H2O2 were studied in the presence of these amino acids and found to be enhanced by them. These results suggest that nickel may specifically produce oxidative DNA damage in heterochromatin because of the nature of its binding to histone H1 and core histones. This selective oxidation of genetically inactive heterochromatin may explain why nickel compounds which generate oxygen radicals and oxidize DNA bases are inactive in most gene mutation assays.
Carcinogenesis 1995 Aug
PMID:Heterochromatic proteins specifically enhance nickel-induced 8-oxo-dG formation. 763

Recent studies have indicated a lack of correlation between hepatic 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels and the carcinogenicity of peroxisome proliferators (PP) and suggested that DNA in intact hepatic nuclei may be insensitive to increases in 8-OHdG resulting from PP exposure. The possibility that PP-induced elevations in acyl CoA oxidase (ACO) activity might result in oxidative damage to mitochondrial DNA (mtDNA) was therefore investigated by feeding male F344 rats the hepatocarcinogenic PP Wy-14,643 (Wy, 0.1% in the diet) for 3, 6, 11, or 22 weeks, or clofibric acid (CA, 0.5% in the diet) for 22 weeks. Following the respective PP exposures, hepatic peroxisomal acyl CoA oxidase activity was determined and DNA isolated from either mitochondria or unfractionated liver homogenates and analysed for the presence of 8-OHdG. PP treatment caused an increase in ACO activity (10- to 15-fold) at all time points examined and an increase of 8-OHdG (1.5- to 2-fold) in DNA isolated from unfractionated liver homogenates following PP treatment for 11 or 22 weeks. No increase of 8-OHdG in mtDNA was detected. However, quantitation of a PCR amplified region from the D-loop of mtDNA demonstrated a 2- to 3-fold increase in the relative amount of mtDNA in DNA isolated from unfractionated liver homogenates following 3, 11, and 22 weeks exposure to Wy or CA (22 weeks only). In addition, a slight increase in the mitochondrial volume density (1.4-fold) was observed in electron micrographs of liver samples from rats exposed to Wy for 22 weeks. These results (i) demonstrate that PP treatment, at levels which cause an increase in ACO activity, does not cause oxidative damage to mtDNA, and (ii) suggest that one reason for the observed increase of 8-OHdG in DNA from unfractionated liver homogenates may be an increase in the amount of mtDNA present in these samples. Furthermore, these studies provide additional evidence against a role of oxidative DNA damage, measured as 8-OHdG, in PP-induced rodent hepatocarcinogenesis and suggest that alterations in mitochondria or other effects may be more pertinent to PP-related carcinogenesis.
Carcinogenesis 1995 Aug
PMID:Elevated 8-hydroxydeoxyguanosine in hepatic DNA of rats following exposure to peroxisome proliferators: relationship to mitochondrial alterations. 763 6

In order to clarify the role of oxidative stress in carcinogenesis by potassium bromate (KBrO3), 8-hydroxydeoxyguanosine (8-OH-dG) levels and cumulating replicating fractions (CRFs) were measured in the kidneys and livers of F344 rats receiving gavage doses of 100, 200 or 400 mg/kg. We used female rats in this study to allow the potential of KBrO3 for inducing alpha 2u-globulin accumulation--known to result in sustained cell proliferation and eventual promoting activity in males--to be ignored. Additional female rats were given 0.05% N-ethyl-N-hydroxyethylnitrosamine (EHEN) orally for the first 2 weeks as an initiator with subsequent administration of KBrO3 at a dose of 500 p.p.m. in the drinking water for 30 weeks. 8-OH-dG levels in the kidneys were significantly elevated with doses of 200 and 400 mg/kg, and this correlated with increases of the CRFs of proximal tubules. In the livers, however, no significant changes were found. In the promotion bioassay, the mean numbers of atypical tubules, atypical hyperplasias and renal cell tumors per rat in animals treated with KBrO3 after EHEN initiation were significantly higher than those in animals receiving distilled water after EHEN initiation. In contrast, there were no significant differences between groups in terms of liver tumors. The overall data suggest that oxidative stress generated by KBrO3 exposure might be associated with induction of cell proliferation and associated promoting activity.
Carcinogenesis 1995 Mar
PMID:A possible role for oxidative stress in potassium bromate (KBrO3) carcinogenesis. 769 18

The present study was aimed at verifying the occurrence, if any, of in vivo oxidative DNA damage in FA homozygotes, their parents and siblings. 8-Hydroxy-2'-deoxyguanosine (8-OHdG) was measured, by HPLC/EC, in DNA from circulating blood leucocytes from FA homozygotes and their relatives and compared with a group of paediatric and adult healthy subjects. The population studied consisted of: (i) 15 FA homozygotes; (ii) 24 FA heterozygotes; (iii) 11 siblings. The 8-OHdG level in FA homozygotes was significantly higher with respect to age-matched controls, with a mean level of 33.3 +/- 6.8 (mean +/- SE) and 3.9 +/- 0.26 8-OHdG/10(5) dG respectively. The FA parents (heterozygotes) also displayed higher 8-OHdG levels relative to controls. The release of hydroxyl (.OH) and .OH-like radicals from leucocytes was determined by luminol-dependent chemiluminescence (LDCL) in a subgroup of FA homo- and heterozygotes, showing a very large in vivo formation of non-superoxide radicals. Chromosomal instability was also measured in the FA population. When relating either 8-OHdG or LDCL levels to spontaneous or diepoxybutane-induced chromosomal instability (S-CI and DEB-CI respectively), a significant correlation was observed between the 8-OHdG, LDCL and S-CI data. Within families a positive association was found between 8-OHdG levels in homozygotes and their related heterozygotes, suggesting segregation of the genetic defect(s) underlying the abnormal oxidative metabolism. The present study provides evidence for an in vivo pro-oxidant state in FA, in terms of excess formation of .OH and .OH-like radicals, and of DNA hydroxyl adducts. This finding appears to be shared by homozygotes and, to a lesser extent, by heterozygotes.
Carcinogenesis 1995 Apr
PMID:In vivo accumulation of 8-hydroxy-2'-deoxyguanosine in DNA correlates with release of reactive oxygen species in Fanconi's anaemia families. 772 50


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