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 levels of 1,N6-ethenodeoxyadenosine (epsilon dAdo) and 3,N4-ethenodeoxycytidine (epsilon dCyd) were measured in DNA of several target organs of vinyl chloride (VC)-exposed rats. Seven-day-old (group I) and 13-week-old (group II) BD VI rats were exposed during 2 weeks to 500 ppm VC in air (7 hr per day and 7 days per week). epsilon dAdo and epsilon dCyd were measured by a combination of prepurification of DNA hydrolysates by HPLC and competitive radioimmunoassay using specific murine monoclonal antibodies. Both ethenodeoxynucleosides were detected in liver, lungs and brain (levels ranging from 0.6 x 10(-7) to 1.3 x 10(-7) for epsilon dAdo/2'-deoxyadenosine and from 1.95 x 10(-7) to 4.92 x 10(-7) for epsilon dCyd/2'-deoxycytidine) but not in kidneys of group I rats. In group II rats, only liver DNA was analysed and the levels of each adduct were six times lower than in young (group II) rats. These findings are in good agreement with the organotropism and the age-related sensitivity of VC-induced carcinogenesis in rodents.
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PMID:Investigations on the relationship between DNA ethenobase adduct levels in several organs of vinyl chloride-exposed rats and cancer susceptibility. 232 97

A sensitive assay for quantitative determination of the vinyl chloride (VC)-induced cyclic DNA adduct N2,3-ethenoguanine (EG) was developed. The method is based on the detection of EG as its di-pentafluorobenzyl derivative (3,5-PFB2-EG). This compound exhibited good gas chromatographic properties and was detected with high sensitivity by gas chromatography with electron capture detection (limit of detection 300 amol/microliters injected solution) or with negative ion chemical ionization mass spectrometry monitoring the [M-181]-fragment ion at m/z 354 (GC-NICI-MS, limit of detection 190 amol/microliters injected solution). EG, its 13C-labeled analog [13C4]-EG and 3,5-PFB2-EG were synthesized and characterized by UV and fluorescence spectrophotometry, 1H- and 13C-NMR spectroscopy and mass spectrometry. The standards were used to optimize the isolation of EG and its derivatization with pentafluorobenzyl bromide (electrophore labeling) at fmol quantities. DNA solutions were spiked with EG, the DNA was depurinated by mild acid hydrolysis, and EG was isolated from the hydrolysates by low-pressure strong cation exchange chromatography with subsequent C18 solid-phase extraction. The extracted EG was electrophore labeled and 3,5-PFB2-EG was detected using GC-NICI-MS. [13C4]EG served as internal standard. 3,5-PFB2-EG was quantitated relative to its 13C-labeled analog by measuring the ion ratio m/z 354/358. The limit of detection for the complete method was 60 fmol EG/mumols guanine. The method was applied to liver DNA from young Sprague-Dawley rats exposed to 600 p.p.m. VC from day 10 through day 14 after birth. The EG concentration in these samples was 1.8 +/- 0.3 pmol/mumols guanine.
Carcinogenesis 1990 Aug
PMID:Vinyl chloride-induced DNA adducts. I: Quantitative determination of N2,3-ethenoguanine based on electrophore labeling. 238 13

The formation and persistence of the DNA adducts 7-(2'-oxoethyl)guanine (OEG) and N2,3-ethenoguanine (EG) were investigated in preweanling Sprague-Dawley rats exposed to vinyl chloride (VC). Lactating female CD rats with 10 day old pups were exposed to 600 p.p.m. VC by inhalation for 5 days, 4 h/day. Groups of rats were killed immediately and 3, 7 and 14 days after exposure. The concentrations of OEG and EG were measured in liver, lung, kidney, brain and spleen. HPLC with fluorescence detection was used for OEG detection, and gas chromatography-negative ion chemical ionization mass spectrometry was used for EG detection. In tissues of neonatal rats, the concentrations of both DNA adducts, expressed as pmol/mumols unmodified guanine, were highest in liver (OEG 162 +/- 36, EG 1.81 +/- 0.25), followed by kidney (OEG 29 +/- 1, EG 0.31 +/- 0.02), and lung (OEG 20 +/- 7, EG 0.21 +/- 0.08). No adducts were found in brain or spleen. DNA adducts were detected only in liver (OEG 43 +/- 7, EG 0.47 +/- 0.14) and lung (OEG 20 +/- 5, EG 0.27 +/- 0.03) of the dams. The ratio between EG and OEG was approximately 1:100 in all tissues immediately after exposure. In the liver of the preweanling rats, this ratio increased to 1:14 1 week after exposure, reflecting a greater persistence of EG. A half-life of 62 h was calculated for OEG, and the estimated half-life for EG was greater than 30 days. In view of the slow loss of EG and its high efficiency for causing base-pair mismatch, these results suggest that EG may be an important DNA adduct in VC-induced carcinogenesis.
Carcinogenesis 1990 Aug
PMID:Vinyl chloride-induced DNA adducts. II: Formation and persistence of 7-(2'-oxoethyl)guanine and N2,3-ethenoguanine in rat tissue DNA. 238 14

1,N6-Etheno-2'-deoxyadenosine (epsilon dAdo) and 3,N4-etheno-2'-deoxycytidine (epsilon dCyd) are formed in vitro by reaction of DNA with the electrophilic metabolites of vinyl chloride (VC), chloroethylene oxide and chloroacetaldehyde. To detect and quantitate these DNA adducts in vivo, we have raised a series of specific monoclonal antibodies (Mab). Among those, Mab EM-A-1 and Mab EM-C-1, respectively, were used for detection of epsilon dAdo and epsilon dCyd by competitive radioimmunoassay (RIA), following pre-separation of the etheno adducts from DNA hydrolysates by high performance liquid chromatography. At 50% inhibition of tracer-antibody binding, both Mab had a detection limit of 187 fmol and antibody affinity constants (K) of 2 x 10(9) l/mol. The levels of epsilon dAdo and epsilon dCyd were quantitated in the DNA of lung and liver tissue of young Sprague-Dawley rats exposed to 2000 p.p.m. of VC for 10 days. The epsilon dAdo/2'-deoxyadenosine and epsilon dCyd/2'-deoxycytidine molar ratios were 1.3 x 10(-7) and 3.3 x 10(-7), respectively, in lung DNA, and 5.0 x 10(-8) and 1.6 x 10(-7) in liver DNA. When hydrolysates of 3 mg of DNA were analyzed by RIA at 25% inhibition of tracer-antibody binding, epsilon dAdo and epsilon dCyd were not detected in liver DNA from untreated rats above the limiting epsilon dAdo/2'-deoxyadenosine and epsilon dCyd/2'-deoxycytidine molar ratios of 2.2 x 10(-8) and 3.1 x 10(-8), respectively.
Carcinogenesis 1989 Jan
PMID:1,N6-etheno-2'-deoxyadenosine and 3,N4-etheno-2'-deoxycytidine detected by monoclonal antibodies in lung and liver DNA of rats exposed to vinyl chloride. 278 95

The development of hepatic enzyme-altered foci (ATPase, GGTase) was investigated after dosing vinyl acetate (200 and 400 mg/kg per day, orally) to newborn rats for 3 weeks, with or without subsequent promotion by phenobarbital. Whereas the structurally related compounds vinyl carbamate and vinyl chloride induce enzyme-altered foci under comparable experimental conditions, no foci were observed in vinyl acetate-treated animals at the age of 14 weeks. This is consistent with investigations on metabolism and pharmacokinetics of vinyl acetate which show that this compound, after entering the organism, is immediately split by blood esterases and thus may not be available for epoxidation to an ultimately carcinogenic metabolite.
Carcinogenesis 1986 May
PMID:Vinyl acetate, a structural analog of vinyl carbamate, fails to induce enzyme-altered foci in rat liver. 287 Aug 25

The age-dependence of the induction of pre-neoplastic enzyme-altered hepatic foci was investigated. Rats were exposed (8 h/day, 7 days/week) to 2000 p.p.m. vinyl chloride (VC) either 'transplacentally' (exposure of pregnant females), or immediately after birth for different time intervals (5, 11, 17, 47, 83 days) or from an age of 7 or 21 days onwards. The animals were then kept without further treatment; livers were evaluated for ATPase-deficient foci at the age of 4 months. 'Transplacental' exposure and exposure from day 1 through 5 caused no increase over controls in ATPase-deficient foci, probably due to the lack of hepatocellular proliferation and the low rate of VC metabolism at this developmental stage. However, foci area was steeply increased when newborn rats were exposed for 11 and 17 days; but this was not further enhanced by a 47- or 83-day exposure. Only a few ATPase-deficient foci occurred when exposure started 21 days after birth. Exposure of adult rats did not result in more ATPase-deficient foci than were seen in untreated controls; control values could not be increased by a preceding partial hepatectomy. The results indicate that the induction of pre-neoplastic hepatocellular lesions in rats by VC is restricted to a well defined period (approximately day 7-21) in the early lifetime of the animals. This period of highest sensitivity is characterized by the beginning of rapid liver growth.
Carcinogenesis 1985 Jan
PMID:The rat liver foci bioassay: I. Age-dependence of induction by vinyl chloride of ATPase-deficient foci. 315 70

In order to study the dose-dependence of the genotoxic effect of vinyl chloride (VC) hepatocellular ATPase-deficient foci were evaluated after subchronic exposure of newborn rats. Wistar rats were exposed from day 1 after birth over 10 weeks to 10, 40, 70, 150, 500 and 2000 p.p.m. VC (8 h/day; 5 days/week). One week after cessation of exposure hepatic ATPase-deficient foci were quantitated. For a subsequent investigation lower dose range groups of female and male Wistar and Sprague-Dawley rats were exposed (8 h/day; 5 days/week) to 2.5, 5, 10, 20, 40 and 80 p.p.m. VC. Exposure started at day 3 of life and lasted for 3 weeks. After cessation of exposure the animals were maintained for 10 weeks without further treatment until ATPase-deficient foci were quantitated. Both sets of experiments revealed a straight linear relationship between the dose of VC and the % foci area induced. Within the dose range investigated, no obvious threshold for the induction of pre-neoplastic foci by VC was observed.
Carcinogenesis 1985 Jan
PMID:The rat liver foci bioassay: II. Investigations on the dose-dependent induction of ATPase-deficient foci by vinyl chloride at very low doses. 315 71

Recent developments in the field of genetic toxicology testing, in particular the outcome of several international collaborative studies, necessitate a re-appraisal of the potential use of Drosophila assays for mutagen testing. For an evaluation of the test performance of the classical sex-linked recessive lethal (SLRL) assay to detect as mutagens mammalian carcinogens, the parameters sensitivity, specificity and accuracy were compared, using as a database the Gene-Tox Report and the results of two international collaborative studies (CSSTT and IPCS). A characteristic of the assay's performance is its low sensitivity (0.33-0.79) and low accuracy (0.50-0.73), when genotoxins other than direct-acting agents and simple promutagens (single-step activation) were included in the analysis. However, the high specificity (0.86-1.0) of the SLRL assay means that in general a positive result has considerable value for prediction of potential genotoxicity in mammals. Experience in the field of carcinogenesis dictates that organ specificity in one species cannot be predicted on the basis of observations in another. It is concluded here that any attempt to use Drosophila assays on the basis of just exposure dose as predictors of effects likely to occur in specific organs in mammals will fail. Examples are provided by the procarcinogens diethylnitrosamine (DEN), vinyl chloride (VC) and hexamethylphosphoramide (HMPA), as well as by the direct-acting mutagens diethylsulphate (DES), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and hycanthone. This view is that it would be highly desirable to compare the Drosophila results on germ cells with in vivo mammalian germ-line tests on the basis of molecular dosimetry studies as proposed by Lee. This approach then should enable the comparison on an adequate basis of mechanism of mutagenesis in Drosophila and rodents. It is specifically concluded that the potential value of the SLRL and any other Drosophila germ-cell assay should be judged against their capability of predicting mammalian genotoxicity in a broad sense but certainly not in specific organs. In this function, germ-line assays will have to compete with the novel tests measuring somatic mutation/mitotic recombination (SMART) in Drosophila. The values obtained for sensitivity (0.75-0.78) and accuracy (0.83-0.86) for the latter tests were clearly better than those found for the SLRL test, suggesting that SMART assays present a promising new development. However, the final judgement of their probable role as complementary or confirmatory methods of genotoxic activity observed in Salmonella must await the outcome of the evaluation studies in progress in several laboratories.
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PMID:Evaluation of potential mammalian genotoxins using Drosophila: the need for a change in test strategy. 332 39

Monoclonal antibodies which specifically recognize ethenoadenosine and ethenocytidine, two of the adducts resulting from exposure to vinyl chloride, have been developed. The sensitivity and specificity of these antibodies have been determined by enzyme-linked immunosorbent assay (ELISA). The antibody to ethenoadenosine (1G4) reacts with both the ribose (50% inhibition at 600 fmol) and deoxyribose (50% inhibition at 980 fmol) form of the adduct. The antibody to ethenocytidine (6F5) also reacts with both the ribose (50% inhibition at 800 fmol) and deoxyribose (50% inhibition at 1000 fmol) form of the adduct. Neither antibody cross-reacts with non-modified DNA or the normal nucleotides. A more sensitive fluorescence ELISA was developed for antibody 1G4 with 50% inhibition at 212 fmol of ethenoadenosine and for antibody 6F5 with 50% inhibition at 192 fmol ethenocytidine. These antibodies have been used to determine the level of etheno derivatives in DNA modified in vitro with chloroacetaldehyde and in the DNA and RNA of cells treated in culture.
Carcinogenesis 1988 Apr
PMID:Development of techniques to monitor for exposure to vinyl chloride: monoclonal antibodies to ethenoadenosine and ethenocytidine. 335 66

Chloroacetaldehyde, the stable metabolite of the human carcinogen vinyl chloride, forms interstrand cross-links in vitro in salmon sperm DNA and in the alternating copolymer, poly(deoxyadenylate-deoxythymidylate) [poly(dA-dT)]. Formation of the cross-link was a function of both time of reaction and concentration of chloroacetaldehyde. Cross-linking in chloroacetaldehyde-treated poly(dA-dT) was detected initially by changes in renaturation hysteresis [Singer et al., Carcinogenesis (Lond.), 5: 1165-1171, 1984]. This has been confirmed and quantitated using the relative fluorescence of ethidium bromide after denaturation and reannealing at 40 degrees C. Three percent cross-linking was detected after 10 min reaction with 20 mM chloroacetaldehyde at 24 degrees C. In DNA the relative fluorescence of ethidium bromide after denaturation and rapid cooling was used to estimate the number of cross-links formed. Three times as much cross-linking occurs in DNA compared to poly(dA-dT) under identical reaction conditions. The postulated structure for an interstrand cross-link in poly(dA-dT) is a hydroxyethyl bridge across the strands between the N6-amino groups of alternate adenine residues. In DNA, other amino groups in the proper configuration can be involved.
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PMID:Formation of interstrand cross-links in chloroacetaldehyde-treated DNA demonstrated by ethidium bromide fluorescence. 340 21


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