Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The capability of Cr(III) to induce DNA lesions generated by oxidative damage was investigated in this study by examining the formation of 8-hydroxydeoxyguanosine (8-OHdG) in calf thymus DNA by CrCl3 and/or H2O2 in 10 mM phosphate buffer. In the presence of 0.5 mM H2O2, the formation of 8-OHdG markedly increased with increasing CrCl3 concentration. In contrast, H2O2 or CrCl3 alone did not cause any increase in 8-OHdG level above background. The amount of 8-OHdG induced by CrCl3 plus H2O2 was time dependent; its generation increased linearly over an incubation period of 90 min. The formation of 8-OHdG was unfavorable in an acidic solution (pH < 6); the highest level of 8-OHdG was observed at pH 7-8. Scavengers of reactive oxygen species markedly inhibited the formation of 8-OHdG by CrCl3 plus H2O2; the inhibition effect was sodium azide > D-mannitol > Tris-HCl at an equal concentration. The induction of 8-OHdG by CrCl3 plus H2O2 remained unchanged in D2O. Moreover, an addition of catalase (2.2 U/ml) to the reaction mixture completely inhibited the formation of 8-OHdG by CrCl3/H2O2, whereas only 22% of that formation was inhibited by superoxide dismutase (11 U/ml). A large amount of bovine serum albumin (1.1 mg/ml) could reduce the formation of 8-OHdG by CrCl3 plus H2O2, thereby implying that Cr(III)-mediated DNA-protein crosslinks are unfavorable for 8-OHdG formation. Furthermore, ascorbate could prevent the formation of 8-OHdG by CrCl3 plus H2O2; the extent of prevention increased with increasing ascorbate concentration (10 microM-3 mM). Thus, ascorbate acts as a free radical scavenger in the CrCl3/H2O2 system. The above findings suggest that Cr(III)/H2O2 could generate oxidative damage to DNA, possibly through a Fenton-like reaction, i.e. Cr(III)+H2O2-->Cr(IV)+.OH+OH-. This study also indicates that Cr(III), previously considered as the ultimate kinetically stable species of Cr(VI) metabolites, is capable of inducing carcinogenic lesions through interaction with a cellular oxygen species.
Carcinogenesis 1996 Jan
PMID:Induction of 8-hydroxydeoxyguanosine in DNA by chromium(III) plus hydrogen peroxide and its prevention by scavengers. 856 17

We have investigated the effect of the soybean isoflavone genistein on 8-hydroxy-2'-deoxyguanosine (8-OHdG) formation in calf thymus DNA exposed to either UV irradiation or the Fenton reaction system. Under the conditions used we observed that UV light and the Fenton reaction significantly increase 8-OHdG formation in DNA. Co-incubation with genistein inhibits the formation of 8-OHdG induced by either UV light irradiation or the Fenton reaction in a dose-dependent manner. The quenching effect of genistein on 8-OHdG formation induced by UV light is much more potent than that by the Fenton reaction, suggesting that the mechanisms of 8-OHdG formation may differ between the two systems. We further compared the antioxidant activities and quenching effect on 8-OHdG formation of genistein with biochanin A. Genistein potently scavenges both hydrogen peroxide in the medium and superoxide anion generated by xanthine/xanthine oxidase, whereas biochanin A has either a weak or no scavenging effect on these reactive oxygen species. However, both genistein and biochanin A display a similar quenching effect on UV light-induced 8-OHdG formation. These results suggest that the quenching effect of genistein and biochanin A on UV light-induced 8-OHdG formation is different from their ability to scavenge hydrogen peroxide and superoxide anion. The potent inhibition of UV light-induced oxidative DNA damage by genistein suggests its potential anticarcinogenic role in photocarcinogenesis.
Carcinogenesis 1996 Jan
PMID:Inhibition of UV light- and Fenton reaction-induced oxidative DNA damage by the soybean isoflavone genistein. 856 40

We have established an animal model for estrogen-induced hepatocarcinogenesis by oral administration of synthetic hormone to female Wistar rats. Daily treatment of rats with 0.15 mg of ethynylestradiol (EE) for 4 months resulted in the development of hyperplastic foci in all animals. At 12 months of EE treatment, four of the 13 rats (30.8%) developed hepatocellular carcinoma. Ornithine decarboxylase (ODC) activity and DNA synthesis in the liver were activated by a single administration of EE, reaching peak levels at 12 and 48 h respectively. The EE-activated peak levels of both ODC activity and DNA synthesis were markedly elevated at 2 months after consecutive treatment, indicating that the female sex hormone stimulates the cellular proliferation during the initiation phase of carcinogenesis. The activities then gradually decreased, but with the levels higher than those in the controls. On the other hand, simultaneous treatment of rats with tamoxifen completely suppressed the EE-induced ODC activity, hepatic foci formation and hepatocellular carcinoma development. Together with our previous findings of DNA adducts and 8-hydroxydeoxyguanosine formation in the early stage of EE-induced carcinogenesis resulting in DNA damage, the present results suggest that estrogen enhanced ODC activity which was followed by increased DNA synthesis (DNA replication). Moreover, these effects might increase misreading during damaged DNA replication and were closely related to initiation, promotion and progression of hepatocarcinogenesis in this experimental model.
Carcinogenesis 1995 Dec
PMID:Role of activation of ornithine decarboxylase and DNA synthesis on ethynylestradiol-induced hepatocarcinogenesis. 860 71

Benzoyl peroxide (BzPO) is a free radical generating compound that acts as a tumor promoter and progressor in mouse skin. BzPO is cleaved in the presence of copper to produce benzoyloxyl and phenyl radicals. Treatment of mutation reporter plasmids with BzPO and copper yields predominantly single-strand breaks and G-->T transversion mutations. To explore the role of base modifications in the possible mammalian mutagenicity of BzPO the formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) within the DNA of cultured murine keratinocytes was investigated. Treatment with 10 microM BzPO produced a maximum 3-fold increase in levels of 8-OHdG versus vehicle controls within 1-2 h, with significant levels of 8-OHdG persisting 6 h after initial exposure to BzPO. Pretreatment with the copper chelator bathocuproine disulfonic acid reduced the levels of 8-OHdG generated by BzPO to near background. However, treatment with the iron chelator desferal did not. The stable metabolic product of BzPO benzoic acid was ineffective in producing 8-OHdG. Depletion of cellular glutathione with L-buthionine-(S,R)-sulfoximine increased the amount of BzPO-generated 8-OHdG, while supplementation with glutathione monoethyl ester reduced the number of 8-OHdG molecules formed. Collectively, these results suggest that BzPO at non-cytotoxic concentrations undergoes copper-dependent activation to a reactive product to generate 8-OHdG within cultured murine keratinocytes.
Carcinogenesis 1996 Feb
PMID:Generation of DNA base modification following treatment of cultured murine keratinocytes with benzoyl peroxide. 862 57

To establish an accurate 8-hydroxydeoxyguanosine (8OHdG) determination system, we examined two potential factors causing experimental error in 8OHdG determination. First, we examined the efficiency of the enzymatic digestion of DNA, that could cause misestimation of 8OHdG. Second, since we considered that the oxygen molecules in atmosphere and in reagents were the main factor contributing to the experimental errors, we carried out the 8OHdG determination under oxygen-free conditions and compared the 8OHdG value with that determined by the methods under ambient atmosphere. The calf thymus DNA was sufficiently digested in the condition we used and the yields of dG were constant, even when the DNA was damaged with H2O2 (80 mM) and UV irradiation. By carrying out the DNA extraction manually, instead of using the DNA extractor, we could reduce the additional 8OHdG formation during sample processing. No trend was found in the difference between the 8OHdG values determined under oxygen-free conditions and under ambient atmosphere. However, when the 8OHdG values were compared in samples with asbestos, the value determined under oxygen-free conditions was significantly lower than that determined under ambient atmosphere. These findings suggest that the removal of oxygen molecules was effective in reducing accidental ROS generation by impurities in the sample, which could cause the additional 8OHdG formation, and that the oxygen-free system made the determination of 8OHdG reproducible and more accurate than before. When the oxygen-free system was applied to human leukocytes, the system showed good reproducibility (r = 0.535, P < 0.001), even though the 8OHdG level was low. With the system, we could detect a significant difference between 8OHdG in polymorphonuclear leukocytes (0.241 +/- 0.129) and mononuclear leukocytes (0.188 +/- 0.126, P < 0.01).
Carcinogenesis 1996 Apr
PMID:Determination of 8-hydroxydeoxyguanosine in human cells under oxygen-free conditions. 862 92

Effects of inhibitors of arachidonic acid (AA) metabolism on the development of fatty liver, cirrhosis, glutathione-S-transferase placental form (GST-P)-positive nodules and the generation of 8-hydroxydeoxyguanosine (8-OHdG) and thiobarbituric acid-reactive substances (TBARS), caused by a choline-deficient, L-amino acid-defined (CDAA) diet, were examined in male Fischer 344 rats by feeding CDAA diets supplemented with the inhibitors for 12 and 30 weeks. Acetylsalicylic acid (ASA) (at doses of 0.1 and 0.2%) and p-bromophenacylbromide (BPB) (0.1 and 0.2%) were used as inhibitors of, respectively, cyclo-oxygenase and phospholipase A2, and quercetin (QU) (0.75 and 1.5%) and nordihydroguaiaretic acid (NDGA) (0.1 and 0.2%) as inhibitors of lipoxygenase. None of the inhibitors affected the development of fatty liver caused by the CDAA diet. ASA at a doe of 0.2% almost completely prevented the appearance of cirrhosis, GST-P-positive nodules, 8-OHdG and TBARS in seven out of 11 (63.7%) rats. BPB at a dose of 0.2% also exerted inhibitory effects on all of these lesions but to a lesser extent than ASA. QU and NDGA exerted inhibitory effects limited to the GST-P-positive nodule case. The results indicate that a perturbed AA metabolism, particularly of the cyclo-oxygenase pathway, derived secondarily from depletion of labile methyl groups or phosphatidylcholine, might play key roles in the cirrhosis, hepatocarcinogenesis and oxidative stress caused by a CDAA diet. The results also indicated a possible involvement of the lipoxygenase pathway in hepatocarcinogenic processes.
Carcinogenesis 1996 Mar
PMID:Inhibition by acetylsalicylic acid, a cyclo-oxygenase inhibitor, and p-bromophenacylbromide, a phospholipase A2 inhibitor, of both cirrhosis and enzyme-altered nodules caused by a choline-deficient, L-amino acid-defined diet in rats. 863 Nov 32

Helicobacter pylori causes type B gastritis. It shows strong association with the development of gastric carcinoma. A plausible hypothesis for the missing link between H. pylori infection and gastric carcinogenesis involves oxygen free radical-induced DNA damage. To test this hypothesis, we compared the amount of 9-hydroxydeoxyguanosine, a marker for oxygen free radical-induced DNA damage, in the DNA of human gastric mucosa with and without H. pylori infection. Gastric antral biopsies were taken from pediatric patients and volunteers to select H. pylori-positive and H. pylori-negative specimens. The 8-hydroxydeoxyguanosine content of the gastric mucosal DNA was measured after H. pylori-positive and H. pylori-negative volunteers were identified. The increased level of oxidative DNA damage suggests the mechanistic link between H. pylori infection and gastric carcinoma.
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PMID:Increased oxidative DNA damage in Helicobacter pylori-infected human gastric mucosa. 864 Aug 14

The objective of the present study was to investigate whether the anticarcinogenic activity of conjugated linoleic acid (CLA) is affected by the amount and composition of dietary fat consumed by the host. Because the anticancer agent of interest is a fatty acid, this approach may provide some insight into its mechanism of action, depending on the outcome of these fat feeding experiments. For the fat level experiment, a custom formulated fat blend was used that simulates the fatty acid composition of the US diet. This fat blend was present at 10, 13.3, 16.7 or 20% by weight in the diet. For the fat type experiment, a 20% (w/w) fat diet containing either corn oil (exclusively) or lard (predominantly) was used. Mammary cancer prevention by CLA was evaluated using the rat dimethylbenz[a]anthracene model. The results indicated that the magnitude of tumor inhibition by 1% CLA was not influenced by the level or type of fat in the diet. It should be noted that these fat diets varied markedly in their content of linoleate. Fatty acid analysis showed that CLA was incorporated predominantly in mammary tissue neutral lipids, while the increase in CLA in mammary tissue phospholipids was minimal. Furthermore, there was no evidence that CLA supplementation perturbed the distribution of linoleate or other fatty acids in the phospholipid fraction. Collectively these carcinogenesis and biochemical data suggest that the cancer preventive activity of CLA is unlikely to be mediated by interference with the metabolic cascade involved in converting linoleic acid to eicosanoids. The hypothesis that CLA might act as an antioxidant was also examined. Treatment with CLA resulted in lower levels of mammary tissue malondialdehyde (an end product of lipid peroxidation), but failed to change the levels of 8-hydroxydeoxyguanosine (a marker of oxidatively damaged DNA). Thus while CLA may have some antioxidant function in vivo in suppressing lipid peroxidation, its anticarcinogenic activity cannot be accounted for by protecting the target cell DNA against oxidative damage. The finding that the inhibitory effect of CLA maximized at 1% (regardless of the availability. of linoleate in the diet) could conceivably point to a limiting step in the capacity to metabolize CLA to some active product(s) which is essential for cancer prevention.
Carcinogenesis 1996 May
PMID:The efficacy of conjugated linoleic acid in mammary cancer prevention is independent of the level or type of fat in the diet. 864 Sep 11

The structure of nuclear chromatin may limit the accessibility of carcinogenic agents to DNA. In the case of oxidative DNA strand cleavage mediated by the physiologically relevant iron chelate, iron-ADP, histone-associated nucleosomal DNA is protected while internucleosomal DNA is susceptible to damage. We now find that the distribution of iron-ADP-generated 8-hydroxydeoxyguanosine, a potentially mutagenic oxidative base change, shows relative targeting to internucleosomal sites (3.5-fold increased oxidative modification of internucleosomal compared with nucleosomal DNA as the minimal degree of enrichment). In contrast, iron-EDTA, which generates hydroxyl radical in the 'fluid phase', does not target internucleosomal DNA. Thus, physiologic iron chelates may promote site-specific damage and thereby be relevant to mechanisms of iron-dependent oxidative mutagenesis and carcinogenesis.
Carcinogenesis 1996 May
PMID:Preferential targeting of oxidative base damage to internucleosomal DNA. 864 Sep 32

To clarify the mechanisms of intracellular induction of oxidative DNA damage, we have investigated the concentrations of intracellular reactive oxygen species and the amounts of 8-hydroxydeoxyguanosine (8OHdG), a mutagenic oxidative DNA damage, in human neutrophil-like cells, dimethylsulfoxide-differentiated HL60 (DMSO-HL60). We determined intracellular concentrations of hydrogen peroxide and superoxide by flow cytometry with dichlorofluorescein diacetate and hydroethidine, respectively. We determined the 8OHdG amounts with an electrochemical detector connected to HPLC after anaerobic sample processing. DMSO-HL60 releases superoxide upon stimulation with phorbol myristate acetate, and the released superoxide dismutates to hydrogen peroxide. Stimulation of DMSO-HL60 with 100 nM phorbol myristate acetate increased intracellular hydrogen peroxide, superoxide and 8OHdG (control). Addition of 1000 U/ml catalase decreased hydrogen peroxide (31.3% of control) and 8OHdG (20.3%). Addition of 100 U/ml SOD decreased superoxide (18.7%) and 8OHdG (41.6%). Addition of 1 mM deferoxamine decreased 8OHdG (30.4%), but increased hydrogen peroxide (129.6%). Addition of 200 microM 4-acetamido-4'- isothiocyanostilbene-2,2'-disulfonic acid decreased superoxide (59.9%) and 8OHdG (42.0%). Addition of 0.4% ethanol had no effect on superoxide concentration (102.2%), but tended to decrease hydrogen peroxide (83.5%) and 8OHdG (84.3%). Pretreatment of DMSO-HL60 with 0.1 mM FeSO4 increased 8OHdG (117.3%), but decreased hydrogen peroxide (75.8%). These findings indicate that the extracellularly released superoxide and hydrogen peroxide diffuse into the cell, but that such reactive oxygen species are not the direct molecules to induce 8OHdG. Our results suggest that 8OHdG is induced by the hydroxyl radical which is generated from intracellular hydrogen peroxide and superoxide-reduced Fe.
Carcinogenesis 1996 Aug
PMID:Relationship between the intracellular reactive oxygen species and the induction of oxidative DNA damage in human neutrophil-like cells. 876 7


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