The Experts below are selected from a list of 234 Experts worldwide ranked by ideXlab platform
Pohgek Forkert - One of the best experts on this subject based on the ideXlab platform.
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mechanisms of lung tumorigenesis by ethyl Carbamate and Vinyl Carbamate
Drug Metabolism Reviews, 2010Co-Authors: Pohgek ForkertAbstract:Vinyl Carbamate (VC) and ethyl Carbamate (EC) induce the formation of lung tumors. The mechanism involves a two-step oxidation of EC to VC and VC to an epoxide, both of which are mediated mainly by CYP2E1. Interaction of the epoxide with DNA leads to the formation of DNA adducts, including 1,N6ethenodeoxyadenosine and 1,N4-ethenodeoxycytidine. The production of DNA adducts correlated with capacities for the bioactivation of VC, which are higher in the lungs of A/J than in C57BL/6 mice. Importantly, CYP2E1 is higher in the lungs of A/J than in C57BL/6 mice. Studies using F1 (Big Blue® × A/J) transgenic mice revealed the formation of mutations in the lambda cII gene after treatment with VC. Mutations induced by VC were mainly A:T→G:C transitions and A:T→T:A transversions, while mutations induced by EC were mainly G:C→A:T transitions. An EC dose that was 17-fold higher than that for VC was required to produce a similar level of mutant frequency in the lung. Pretreatment of mice with the CYP2E1 inhibitor, dia...
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inhibition of Vinyl Carbamate induced lung tumors and kras2 mutations by the garlic derivative diallyl sulfone
Mutation Research, 2009Co-Authors: Lya G Hernandez, Pohgek ForkertAbstract:Abstract Vinyl Carbamate (VC) is derived from ethyl Carbamate (EC), a chemical found in alcoholic beverages and fermented foods. The objectives of this study were to characterize the formation of lung tumors induced by VC in F 1 (Big Blue ® x A/J) mice, and to identify the mutations formed in the K ras 2 gene. In addition, we have tested the hypothesis that pretreatment with diallyl sulfone (DASO 2 ) inhibits the adverse effects of VC. Mice were treated with VC (60 mg/kg, i.p.) or DASO 2 (50 mg/kg, p.o.) 2 h prior to VC (DASO 2 /VC). Lung tumor multiplicity was significantly lower (21%) in mice treated with DASO 2 /VC than with VC. Lung tumors induced by VC are manifested as solid or papillary tumors, with the latter being regarded as a more malignant phenotype as they demonstrate no growth restrictions. Solid (42%) and papillary tumors (58%) were found in similar proportions in VC-treated mice. The number of papillary tumors was significantly decreased (44.5%) in mice treated with DASO 2 /VC, while there was a proportional increase (44.5%) in the number of solid tumors. The number of tumors with mutations in the first and second exon of K ras 2 was significantly lower after treatment with DASO 2 /VC (7%) than after treatment with VC (61%). The mutations were mainly found in codon 61, and were identified as A → T transversions (31%) and A → G transitions (25%) in the second base, and A → T transversions (12%) in the third base. All of these mutations were significantly reduced by DASO 2 pretreatment. The number of tumors containing K ras 2 mutations was highest (38%) in the large papillary tumors. Hence, mice treated with DASO 2 /VC had decreased frequencies of K ras 2 mutations and reduced numbers of small and large papillary tumors, suggesting that activation of the K ras 2 gene may be implicated in lung tumor formation and progression.
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inhibition of Vinyl Carbamate induced mutagenicity and clastogenicity by the garlic constituent diallyl sulfone in f1 big blue a j transgenic mice
Carcinogenesis, 2007Co-Authors: Lya G Hernandez, Pohgek ForkertAbstract:Vinyl Carbamate (VC) is a metabolite of ethyl Carbamate (EC), a naturally occurring compound found in fermented foods and alcoholic beverages. CYP2E1 mediates the sequential oxidation of EC to VC and subsequently to the Vinyl Carbamate epoxide, which is believed to be the ultimate carcinogenic species. Here, we have tested the hypothesis that bioactivation of VC by CYP2E1 plays a central role in the development of its mutagenicity and clastogenicity, and further that inhibition of CYP2E1 by diallyl sulfone (DASO 2 ) leads to diminution in their incidences. DASO 2 is a garlic constituent that is oxidized by CYP2E1, leading to inactivation of this P450. F 1 (Big Blue ® × A/J) transgenic mice harboring the λ cII gene were used for in vivo identification and quantitation of mutations in the lung and small intestine. Mice were pre-treated with DASO 2 (12.5-200 mg/kg, p.o.), treated 2 h later with VC (60 mg/kg, i.p.) and were killed 4 weeks later. Our results showed that pre-treatment of mice with DASO 2 at doses of 50-200 mg/kg significantly decreased the VC-induced mutant frequencies (MFs) by 50-70%. In the small intestine, pre-treatment with 200 mg/kg of DASO 2 decreased the MF by ∼40%. Clastogenicity, as assessed by the frequency of micronucleated reticulocytes, was significantly decreased (33-44%) by pre-treatment with DASO 2 (50-200 mg/kg). These results demonstrated that bioactivation of VC by CYP2E1 plays a valid role in the development of mutagenicity and clastogenicity, and further that inhibition of this pathway by DASO 2 produces a protective effect.
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oxidation of Vinyl Carbamate and formation of 1 n6 ethenodeoxyadenosine in murine lung
Drug Metabolism and Disposition, 2007Co-Authors: Pohgek Forkert, Martin Kaufmann, Gordon P Black, Raymond J Bowers, Heidi Chen, Kathy S Collins, Ashish Sharma, Glenville JonesAbstract:Vinyl Carbamate (VC) is derived from ethyl Carbamate, a carcinogen formed in fermentation of food and alcoholic products. We have undertaken studies to test the hypothesis that an epoxide generated from VC oxidation leads to formation of 1,N 6 -ethenodeoxyadenosine (dAS). We have developed approaches using liquid chromatography-mass spectrometry and liquid chromatographytandem mass spectrometry for identification and quantitation of dAS. Scanning and fragment ion analyses confirmed the identity of dAS based on the molecular ion [M H] m/z 276 and the specific fragment ion m/z 160. Chemical oxidation of VC in reactions containing 2� -deoxyadenosine produced dAS with 1 H NMR, chromatographic, and mass spectral characteristics identical to those of the authentic dAS, suggesting DNA alkylation by the VC epoxide. Subsequent studies evaluated formation of dAS in incubations of murine lung microsomes or recombinant CYP2E1 with VC. The formation of dAS in incubations of lung microsomes or recombinant CYP2E1 with VC was dependent on protein concentrations, CYP2E1 enzyme levels, and incubation time. The rates of dAS formation were highly correlated with VC concentrations. Peak rates were produced by lung microsomes and recombinant CYP2E1 at 3.0 and 2.5 mM VC, respectively. In inhibitory studies, incubations of VC were performed using lung microsomes from mice treated with the CYP2E1 inhibitor diallyl sulfone (100 mg/kg, p.o.). Results from these studies showed significantly decreased dAS formation in microsomes incubated with VC, with an inhibition of 70% at 3.0 mM. These findings suggested that CYP2E1 is a major enzyme mediating VC oxidation, leading to the formation of a metabolite that alkylates DNA to form the dAS adduct.
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in vivo mutagenicity of Vinyl Carbamate and ethyl Carbamate in lung and small intestine of f1 big blue x a j transgenic mice
International Journal of Cancer, 2007Co-Authors: Lya G Hernandez, Pohgek ForkertAbstract:Vinyl Carbamate (VC) is a metabolite of ethyl Carbamate (EC), a chemical found in alcoholic beverages and fermented foods. We undertook this study to: (i) evaluate the ability of both EC and VC to induce gene mutations in lung and various extrapulmonary tissues, and (ii) identify the type of mutations induced by the two compounds in various tissues. F1 (Big Blue® × A/J) transgenic mice harboring the lambda cII transgene were used for identification and quantitation of mutations in vivo. Time-course studies in lung showed a plateau in mutant frequency (MF) 4 weeks after VC treatment, at which time mutations were fixed and were about 4-fold higher than in controls. Dose-dependent increases in MF were detected in the lung and small intestine (SI) after treatment with 15–75 mg/kg, i.p., of VC. VC was mutagenic in the lung and SI at doses of 45, 60 and 75 mg/kg. Sequencing of the cII gene in lung and SI showed that VC induced mainly A:TG:C transitions and A:TT:A transversions. EC was also mutagenic in the lung at 500 and 1,000 mg/kg and elicited mainly G:CA:T transitions. A VC dose of 60 mg/kg elicited a similar level of MF as an EC dose of 1,000 mg/kg. At 4 weeks after treatment, neither VC nor EC elicited mutations in the colon, bone marrow or kidney. These results demonstrated that VC and EC are mutagenic in vivo and affirm that VC is a more potent mutagen than EC. © 2006 Wiley-Liss, Inc.
Robert R Maronpot - One of the best experts on this subject based on the ideXlab platform.
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Carcinogen-specific targeting of chromosome 12 for loss of heterozygosity in mouse lung adenocarcinomas: implications for chromosome instability and tumor progression
Oncogene, 2004Co-Authors: Christopher R. Herzog, Robert R Maronpot, Thomas E Massey, Marshall W Anderson, Brian Pittman, Nomar Bodon, Theodora R DevereuxAbstract:Genotoxic carcinogens exert their tumorigenic effects in part by inducing genomic instability. We recently showed that loss of heterozygosity (LOH) on chromosome 12 associates significantly with the induction of chromosome instability (CIN) by the likely human lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and Vinyl Carbamate (VC) during mouse lung carcinogenesis. Here, we demonstrate the carcinogen specificity of this event and its effect on lung tumor evolution. LOH on chromosome 12 was observed in 45% of NNK-induced, 59% of VC-induced, 58% of aflatoxin B1 (AFB1)-induced, 14% of N -ethyl- N -nitrosourea (ENU)-induced and 12% of spontaneous lung adenocarcinomas. The frequency of LOH in each of the carcinogen-induced groups, except ENU, was significantly higher than in the spontaneous group ( P
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comparative prevalence multiplicity and progression of spontaneous and Vinyl Carbamate induced liver lesions in five strains of male mice
Toxicologic Pathology, 2002Co-Authors: Kimimasa Takahashi, Gregg E Dinse, Julie F Foley, Jerry F Hardisty, Robert R MaronpotAbstract:The overall and age-specic prevalences and multiplicities of spontaneou s and chemically induced hepatocellular neoplasia were compared among male B6D2F1, B6C3F1, C3H (C3H/HeNCrl MTV-), B6CF1, and C57BL/6 (C57BL/6NCrl) mice following a single intraperitoneal injection of 0.03 l M Vinyl Carbamate (VC)/g body weight or vehicle alone at 15 days of age. Additional groups of B6C3F1, C3H, and C57BL/6 males received 0.15 l M VC/g body weight at 15 days of age. For male B6D2F1, B6C3F1, C3H, B6CF1, and C57BL/6 mice, the estimated overall prevalences (and multiplicities) of hepatocellular adenomas or carcinomas in vehicle controls were 14.1% (0.19), 12.3% (0.15), 8.2% (0.10), 7.2% (0.09), and 2.4% (0.02), respectively. The analogous estimates in the low-dose group were 59.2% (1.19), 72.9% (4.07), 48.6% (1.99), 22.8% (0.29), and 43.9% (0.82). Analogous estimates for B6C3F1, C3H, and C57BL/6 mice in the high-dose group were 45.3% (4.29), 59.7% (6.63), and 46.8% (1.74), respectively. Age-specic multiplicity estimates suggested a progression from altered hepatocellular foci (AHF) to hepatocellular neoplasms. Further evidence of progression was provided by the temporal occurrence of hepatocellular adenomas before carcinomas, and the apparent origination of carcinomas within adenomas. Pulmonary metastases were observed in many of the mice with hepatocellular carcinomas. These ndings con rm previous observations of strain differences in liver neoplasm response, suggest a progressive developmen t from AHF to adenomas, and ultimately to carcinomas, and show sensitivity to VC-induced hepatocarcinogenesi s in all 5 strains.
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susceptibility of transgenic mice carrying human prototype c ha ras gene in a short term carcinogenicity study of Vinyl Carbamate and ras gene analyses of the induced tumors
Molecular Carcinogenesis, 1997Co-Authors: Kunitoshi Mitsumori, Kazuo Yasuhara, Shigeharu Wakana, Satoshi Yamamoto, Yukio Kodama, Tatsuji Nomura, Yuzo Hayashi, Robert R MaronpotAbstract:To determine if hemizygous transgenic mice carrying the human c-Ha-ras gene (CB6F1-Tg Hras2 mice (Hras2 mice)) are susceptible to the carcinogenic potential of known murine carcinogens, male and female Hras2 mice and their non-transgenic CB6F1 littermates (non-Tg mice) were each given a single intraperitoneal injection of 60 mg of Vinyl Carbamate (VC)/kg body weight or saline (vehicle control) and monitored for 16 wk without further treatment. At necropsy, grossly visible tumors were fixed for histopathologic diagnosis and, when of sufficient size, portions were frozen for subsequent molecular analysis. Nine of 31 male and nine of 29 female Hras2 mice treated with VC died within 16 wk as a result of lung tumor burden. At the termination of the study, lung tumors (alveolar-bronchiolar epithelial neoplasms and hemangiosarcomas) and focal alveolar-bronchiolar hyperplasias were present in both sexes of Hras2 and non-Tg mice treated with VC; there were significantly more proliferative lung lesions in Hras2 than non-Tg mice. Splenic hemangiosarcomas and squamous cell tumors of the forestomach were induced in male and female VC-treated Hras2 mice but not in VC-treated non-Tg mice. Polymerase chain reaction–single-strand conformation polymorphism analysis and DNA sequencing of the induced lung tumors revealed point mutations at codon 61 of the transgene in two of 29 lung tumors (one of 16 in males and one of 13 in females) from VC-treated Hras2 mice; no mutations in murine Ki-ras were found in these tumors. Point mutations at codons 12 and 61 of the murine Ki-ras gene were observed, however, in one of 10 and six of 10 lung tumors respectively, from VC-treated non-Tg mice. These findings indicate that Hras2 mice are highly sensitive to pulmonary neoplasms and splenic and lung hemangiosarcomas after treatment with VC. The molecular analyses suggest that point mutations of the transgene and the murine Ki-ras gene do not play a major role in VC induction of pulmonary neoplasms in these transgenic mice. Mol. Carcinog. 20:298–307, 1997. © 1997 Wiley-Liss, Inc.
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h ras oncogene mutation spectra in b6c3f1 and c57bl 6 mouse liver tumors provide evidence for tcdd promotion of spontaneous and Vinyl Carbamate initiated liver cells
Carcinogenesis, 1995Co-Authors: Mary A Watson, Theodora R Devereux, David E Malarkey, M W Anderson, Robert R MaronpotAbstract:2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent environmental toxin which has been found to be non-genotoxic in short term in vitro tests but strongly carcinogenic in two stage models of hepatocellular carcinogenesis in female rats. Many recent studies have shown that after treatment of mice with various genotoxic or non-genotoxic compounds, the H-ras oncogene mutational patterns exhibited by hepatocellular tumors appear to vary specifically with the chemical. To gain insight into the mechanism of TCDD-associated carcinogenesis, susceptible B6C3F1 mice and resistant C57BL/6 mice were treated with a single dose of Vinyl Carbamate (VC) or vehicle, and TCDD was administered once every 2 weeks for 1 year to half of the animals in each group. Liver tumor prevalence was assessed and found to be highest in the VC+TCDD treatment groups, reaching nearly 100% at 600 days in both sexes and both strains of mice. DNA was isolated from 20 or more frozen liver tumors (if available) from each exposure group and analyzed for H-ras mutations in codon 61 by sequencing after PCR amplification of exon 2. Fifty-one percent of tumors analyzed from B6C3F1 mice treated with TCDD alone had H-ras codon 61 mutations with a pattern similar to that detected in spontaneous tumors. Seventy-eight percent of tumors from B6C3F1 mice treated with both VC and TCDD had codon 61 mutations, and most mutations were A→T transversions in the second base as observed similarly with VC alone. In the C57BL/6 strain comparable results were found in the respective exposure groups. These data suggest that TCDD is acting as a promoter of lesions previously initiated either spontaneously or by VC. Moreover, the intrinsic resistance of both male and female C57BL/6 mice to liver tumor formation seemed to disappear after treatment with TCDD.
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H-ras oncogene mutation spectra in B6C3F1 and C57BL/6 mouse liver tumors provide evidence for TCDD promotion of spontaneous and Vinyl Carbamate-initiated liver cells
Carcinogenesis, 1995Co-Authors: Mary A Watson, Theodora R Devereux, David E Malarkey, M W Anderson, Robert R MaronpotAbstract:2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent environmental toxin which has been found to be non-genotoxic in short term in vitro tests but strongly carcinogenic in two stage models of hepatocellular carcinogenesis in female rats. Many recent studies have shown that after treatment of mice with various genotoxic or non-genotoxic compounds, the H-ras oncogene mutational patterns exhibited by hepatocellular tumors appear to vary specifically with the chemical. To gain insight into the mechanism of TCDD-associated carcinogenesis, susceptible B6C3F1 mice and resistant C57BL/6 mice were treated with a single dose of Vinyl Carbamate (VC) or vehicle, and TCDD was administered once every 2 weeks for 1 year to half of the animals in each group. Liver tumor prevalence was assessed and found to be highest in the VC+TCDD treatment groups, reaching nearly 100% at 600 days in both sexes and both strains of mice. DNA was isolated from 20 or more frozen liver tumors (if available) from each exposure group and analyzed for H-ras mutations in codon 61 by sequencing after PCR amplification of exon 2. Fifty-one percent of tumors analyzed from B6C3F1 mice treated with TCDD alone had H-ras codon 61 mutations with a pattern similar to that detected in spontaneous tumors. Seventy-eight percent of tumors from B6C3F1 mice treated with both VC and TCDD had codon 61 mutations, and most mutations were A→T transversions in the second base as observed similarly with VC alone. In the C57BL/6 strain comparable results were found in the respective exposure groups. These data suggest that TCDD is acting as a promoter of lesions previously initiated either spontaneously or by VC. Moreover, the intrinsic resistance of both male and female C57BL/6 mice to liver tumor formation seemed to disappear after treatment with TCDD.
Theodora R Devereux - One of the best experts on this subject based on the ideXlab platform.
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Aberrant Promoter Hypermethylation of the Death-Associated Protein Kinase Gene Is Early and Frequent in Murine Lung Tumors Induced by Cigarette Smoke and Tobacco Carcinogens
Cancer Research, 2004Co-Authors: Leah C. Pulling, Theodora R Devereux, Brian R. Vuillemenot, Julie A. Hutt, Steven A. BelinskyAbstract:Loss of expression of the death-associated protein (DAP)-kinase gene by aberrant promoter methylation may play an important role in cancer development and progression. The purpose of this investigation was to determine the commonality for inactivation of the DAP-kinase gene in adenocarcinomas induced in mice by chronic exposure to mainstream cigarette smoke, the tobacco carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and Vinyl Carbamate, and the occupational carcinogen methylene chloride. The timing for inactivation was also determined in alveolar hyperplasias that arise in lung cancer induced in the A/J mouse by NNK. The DAP-kinase gene was not expressed in three of five NNK-induced lung tumor-derived cell lines or in a spontaneously arising lung tumor-derived cell line. Treatment with 5-aza-2'-deoxycytidine restored expression; dense methylation throughout the DAP-kinase CpG island detected by bisulfite sequencing supported methylation as the inactivating event in these cell lines. Methylation-specific PCR detected inactivation of the DAP-kinase gene in 43% of tumors associated with cigarette smoke, a frequency similar to those reported in human non-small cell lung cancer. In addition, DAP-kinase methylation was detected in 52%, 60%, and 50% of tumors associated with NNK, Vinyl Carbamate, and methylene chloride, respectively. Methylation was observed at similar prevalence in both NNK-induced hyperplasias and adenocarcinomas (46% versus 52%), suggesting that inactivation of this gene is one pathway for tumor development in the mouse lung. Bisulfite sequencing of both premalignant and malignant lesions revealed dense methylation, substantiating that this gene is functionally inactivated at the earliest histological stages of adenocarcinoma development. This study is the first to use a murine model of cigarette smoke-induced lung cancer and demonstrate commonality for inactivation by promoter hypermethylation of a gene implicated in the development of this disease in humans.
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Carcinogen-specific targeting of chromosome 12 for loss of heterozygosity in mouse lung adenocarcinomas: implications for chromosome instability and tumor progression
Oncogene, 2004Co-Authors: Christopher R. Herzog, Robert R Maronpot, Thomas E Massey, Marshall W Anderson, Brian Pittman, Nomar Bodon, Theodora R DevereuxAbstract:Genotoxic carcinogens exert their tumorigenic effects in part by inducing genomic instability. We recently showed that loss of heterozygosity (LOH) on chromosome 12 associates significantly with the induction of chromosome instability (CIN) by the likely human lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and Vinyl Carbamate (VC) during mouse lung carcinogenesis. Here, we demonstrate the carcinogen specificity of this event and its effect on lung tumor evolution. LOH on chromosome 12 was observed in 45% of NNK-induced, 59% of VC-induced, 58% of aflatoxin B1 (AFB1)-induced, 14% of N -ethyl- N -nitrosourea (ENU)-induced and 12% of spontaneous lung adenocarcinomas. The frequency of LOH in each of the carcinogen-induced groups, except ENU, was significantly higher than in the spontaneous group ( P
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Carcinogenic Induction Directs the Selection of Allelic Losses in Mouse Lung Tumorigenesis
Cancer Research, 2002Co-Authors: Christopher R. Herzog, Theodora R Devereux, Brian PittmanAbstract:Recent evidence suggests that genome-wide allelic imbalances are inducible by carcinogens and may occur as cells adapt to carcinogenic exposure during tumorigenesis. We investigated the role of carcinogenic exposure on global and selected loss of heterozygosity (LOH) during mouse lung adenocarcinogenesis. Tumor induction by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) or Vinyl Carbamate (VC) resulted in a significant overall increase in the number of chromosomes affected by LOH per tumor when compared with spontaneous lung tumors. Allelic loss on chromosome 12 occurred at a frequency of 35% and 40% in NNK- and VC-induced tumors, respectively, compared with 8.3% in spontaneous tumors ( P P
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Mutation of β-catenin is an early event in chemically induced mouse hepatocellular carcinogenesis
Oncogene, 1999Co-Authors: Theodora R Devereux, Julie F Foley, Colleen H Anna, Catherine M White, Robert C Sills, J Carl BarrettAbstract:β-catenin activation, and subsequent upregulation of Wnt-signaling, is an important event in the development of certain human and rodent cancers. Recently, mutations in the β-catenin gene in the region of the serine-threonine glycogen kinase (GSK)-3β phosphorylation target sites have been identified in hepatocellular neoplasms from humans and transgenic mice. In this study we examined 152 hepatocellular neoplasms from B6C3F1 mice included in five chemical treatment groups and controls for mutations in the β-catenin gene. Twenty of 29 hepatocellular neoplasms from mice treated with methyleugenol had point mutations at codons 32, 33, 34 or 41, sites which are mutated in colon and other cancers. Likewise, nine of 24 methylene chloride-induced hepatocellular neoplasms and 18 of 42 oxazepam-induced neoplasms exhibited similar mutations. In contrast, only three of 18 Vinyl Carbamate-induced liver tumors, one of 18 TCDD-induced liver tumors, and two of 22 spontaneous liver neoplasms had mutations in β-catenin. Thus, there appears to be a chemical specific involvement of β-catenin activation in mouse hepatocellular carcinogenesis. Expression analyses using Western blot and immunohistochemistry indicate that β-catenin protein accumulates along cell membranes following mutation. The finding of mutations in both adenomas and carcinomas from diverse chemical treatment groups and the immunostaining of β-catenin protein in an altered hepatocellular focus suggest that these alterations are early events in mouse hepatocellular carcinogenesis.
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h ras oncogene mutation spectra in b6c3f1 and c57bl 6 mouse liver tumors provide evidence for tcdd promotion of spontaneous and Vinyl Carbamate initiated liver cells
Carcinogenesis, 1995Co-Authors: Mary A Watson, Theodora R Devereux, David E Malarkey, M W Anderson, Robert R MaronpotAbstract:2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent environmental toxin which has been found to be non-genotoxic in short term in vitro tests but strongly carcinogenic in two stage models of hepatocellular carcinogenesis in female rats. Many recent studies have shown that after treatment of mice with various genotoxic or non-genotoxic compounds, the H-ras oncogene mutational patterns exhibited by hepatocellular tumors appear to vary specifically with the chemical. To gain insight into the mechanism of TCDD-associated carcinogenesis, susceptible B6C3F1 mice and resistant C57BL/6 mice were treated with a single dose of Vinyl Carbamate (VC) or vehicle, and TCDD was administered once every 2 weeks for 1 year to half of the animals in each group. Liver tumor prevalence was assessed and found to be highest in the VC+TCDD treatment groups, reaching nearly 100% at 600 days in both sexes and both strains of mice. DNA was isolated from 20 or more frozen liver tumors (if available) from each exposure group and analyzed for H-ras mutations in codon 61 by sequencing after PCR amplification of exon 2. Fifty-one percent of tumors analyzed from B6C3F1 mice treated with TCDD alone had H-ras codon 61 mutations with a pattern similar to that detected in spontaneous tumors. Seventy-eight percent of tumors from B6C3F1 mice treated with both VC and TCDD had codon 61 mutations, and most mutations were A→T transversions in the second base as observed similarly with VC alone. In the C57BL/6 strain comparable results were found in the respective exposure groups. These data suggest that TCDD is acting as a promoter of lesions previously initiated either spontaneously or by VC. Moreover, the intrinsic resistance of both male and female C57BL/6 mice to liver tumor formation seemed to disappear after treatment with TCDD.
James A Miller - One of the best experts on this subject based on the ideXlab platform.
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chemopreventive effects of 2 allylthio pyrazine on hepatic lesion mutagenesis and tumorigenesis induced by Vinyl Carbamate or Vinyl Carbamate epoxide
Carcinogenesis, 1998Co-Authors: Youngjoon Surh, Kiyu Park, Yeowon Sohn, James A MillerAbstract:2-(Allylthio)pyrazine (2-AP), synthesized for its possible use as a hepatoprotective agent, has been found to selectively inhibit rat hepatic cytochrome P450 2E1 (Kim et al., Biochem. Pharmacol., 53, 261-269, 1997), while it enhances the activities of phase II detoxification enzymes such as glutathione S-transferase and epoxide hydrolase. As part of a program in evaluating the chemopreventive potential of 2-AP, we have determined its effects on hepatotoxicity, mutagenicity and tumorigenicity of Vinyl Carbamate (VC), a prototypic hepatocarcinogen preferentially activated by P450 2E1 to the ultimate carcinogenic metabolite Vinyl Carbamate epoxide (VCO), which undergoes detoxification by glutathione conjugation and oxirane hydrolysis. Administration of 2-AP (100 mg/kg body wt) to male Sprague-Dawley rats by gavage, 2 days, 1 day and 4 h prior to VC or VCO, markedly ameliorated the hepatotoxicity of these compounds as determined by decreased serum aspartate aminotransferase and alanine aminotransferase activities. Furthermore, 2-AP pre-treatment significantly suppressed the VC-induced hepatocarcinogenesis in infant male B6C3F 1 mice. In a separate experiment, the multiplicities of skin tumors formed in female ICR mice treated with 5.8 μmol of VC or VCO were inhibited 58 and 70%, respectively, by pre-treatment with 2-AP by oral administration. The mutational spectrum of ras-oncogene in papillomas was not altered by 2-AP pre-treatment. 2-AP also inhibited the mutagenicity of VC in the Salmonella-microsome assay. Taken together, these findings suggest that 2-AP is a potential chemopreventive agent.
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inhibition of Vinyl Carbamate induced hepatotoxicity mutagenicity and tumorigenicity by isopropyl 2 1 3 dithietane 2 ylidene 2 n 4 methylthiazol 2 yl carbamoyl acetate yh439
Carcinogenesis, 1998Co-Authors: Youngjoon Surh, Amy Liem, Yeowon Sohn, James A MillerAbstract:Isopropyl-2-(1,3-dithietane-2-ylidene)-2-[N-(4-methylthiazol-2-yl)carbamoyl]acetate (YH439) is a novel dithioylidene malonate derivative developed for the treatment of hepatic injury. The compound has been found to down-regulate the expression of hepatic cytochrome P-450 2E1 (CYP2E1) at the transcriptional level (8). Certain organosulfur compounds present in garlic elicit protective effects on chemically induced carcinogenesis and mutagenesis and their chemopreventive activities are associated in part with inhibition of CYP2E1. As part of a program to determine the likely chemopreventive potential of YH439, we initially examined its effects on hepatotoxicity induced by Vinyl Carbamate (VC), a proximate carcinogen that is preferentially bioactivated by CYP2E1. A single i.p. injection of VC (125 mg/kg body wt) to male Sprague-Dawley rats resulted in severe hepatic lesions as demonstrated by elevated levels of serum enzymes such as alanine aminotransferase and aspartate aminotransferase. Histopathological evaluation of liver sections from VC-treated animals revealed that the hepatic damage mainly consisted of centrilobular necrosis with sinusoidal congestion. Oral administration of YH439 (200 mg/kg body wt) to male Sprague-Dawley rats 2 days, 1 day and 4 h prior to VC completely prevented the hepatic damage caused by this carcinogen. In another experiment, rat hepatic microsome-mediated bacterial mutagenicity of VC was suppressed by YH439 in a dose-related manner. Furthermore, pretreatment of female CD-1 mice with YH439 by gastric intubation resulted in diminution of VC-induced skin carcinogenesis.
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chemoprotective effects of capsaicin and diallyl sulfide against mutagenesis or tumorigenesis by Vinyl Carbamate and n nitrosodimethylamine
Carcinogenesis, 1995Co-Authors: Youngjoon Surh, Kwangkyun Park, Amy Liem, Susan Taylor Mayne, James A MillerAbstract:Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is a major pungent and irritating ingredient of hot chilli peppers, which are frequently consumed as spices. This dietary phytochemical has been found to interact with microsomal xenobiotic metabolizing enzymes in rodents. Capsaicin and its saturated analog dihydrocapsaicin (trans8-methyl-N-vanillyl-6-nonanamide) have been proposed to inactivate cytochrome P-450 IIE1 by irreversibly binding to the active sites of the enzyme. Besides cytochrome P-450 IIE1, other isoforms of the P-450 superfamily were also reported to be inhibited by capsaicin. The inhibition by capsaicin of microsomal monooxygenases involved in carcinogen activation implies its chemopreventive potential. As part of a program to investigate chemoprotective properties of capsaicin we initially determined the effect of capsaicin on Vinyl Carbamate (VC)- and N-nitrosodimethylamine (NDMA)-induced mutagenesis in Salmonella typhimurium TA100. Capsaicin (0.42 mM) attenuated the bacterial mutagenicity of VC and NDMA by 50% and 42% respectively. Diallyl sulfide, a thioether found in garlic with selective P-450 IIE1 inhibitory activity, also lessened the mutagenicity of the above carcinogens in a concentration-dependent manner. The suppression of VC- and NDMA-induced mutagenesis by capsaicin and diallyl sulfide correlated with their inhibition of P-450 IIE1-mediated p-nitrophenol hydroxylation and NDMA N-demethylation. Pretreatment of female ICR mice with a topical dose of capsaicin lowered the average number of VC-induced skin tumors by 62% at 22 weeks after promotion. A similar degree of protection was attained with oral administration of diallyl sulfide before carcinogen treatment. The results of this study suggest that capsaicin and diallyl sulfide suppress VC- and NDMA-induced mutagenesis or tumorigenesis in part through inhibition of the cytochrome P-450 IIE1 isoform responsible for activation of these carcinogens.
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chemoprotective properties of chlorophyllin against Vinyl Carbamate p nitrophenyl Vinyl ether and their electrophilic epoxides
Cancer Letters, 1995Co-Authors: Kwangkyun Park, Youngjoon Surh, James A MillerAbstract:Abstract Chlorophyllin (CHL), a water-soluble sodium and copper derivative of chlorophyll, has been shown to be a strong antimutagen in several test systems, but its mechanism of antimutagenic action is largely unknown. In the present study, we have found the protective properties of CHL against Vinyl Carbamate, p -nitrophenyl Vinyl ether and their electrophilic epoxides. CHL exhibited dose-related inhibition of his + reversion in Salmonella typhimurium TA 1535 induced by these mutagens. Formation of DNA adducts from Vinyl Carbamate epoxide (VCO) and 2′-(4-nitrophenoxy)oxirane (NPO) was also markedly attenuated in the presence of CHL. Oral administration of CHL prior to the topical application of each of the above carcinogens resulted in significant reduction in both incidence and multiplicity of skin tumors in mice. The effective protection by CHL against VCO and NPO suggest that its formation of inactive complexes with these carcinogens is mediated by mechanisms other than π-π interactions.
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Vinyl Carbamate epoxide a major strong electrophilic mutagenic and carcinogenic metabolite of Vinyl Carbamate and ethyl Carbamate urethane
Carcinogenesis, 1993Co-Authors: Kwangkyun Park, Bradley C Stewart, Amy Liem, James A MillerAbstract:Vinyl Carbamate epoxide (VCO) was found to possess strong electrophilic, mutagenic and carcinogenic activities. It reacted with water at 37 o C and pH 7.4 (phosphate buffer) to form glycolaldehyde and several related reducing compounds; none of these products were mutagenic for Salmonella typhimurium TA1535. Under these conditions VCO had a half-life (determined chemically and mutagenically) of -10.5 min. This half-life was progressively lowered by increasing concentrations of chloride ion (liver, serum and isotonic levels). This ion reacted with VCO to form chloroacetaldehyde
Marshall W Anderson - One of the best experts on this subject based on the ideXlab platform.
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Carcinogen-specific targeting of chromosome 12 for loss of heterozygosity in mouse lung adenocarcinomas: implications for chromosome instability and tumor progression
Oncogene, 2004Co-Authors: Christopher R. Herzog, Robert R Maronpot, Thomas E Massey, Marshall W Anderson, Brian Pittman, Nomar Bodon, Theodora R DevereuxAbstract:Genotoxic carcinogens exert their tumorigenic effects in part by inducing genomic instability. We recently showed that loss of heterozygosity (LOH) on chromosome 12 associates significantly with the induction of chromosome instability (CIN) by the likely human lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and Vinyl Carbamate (VC) during mouse lung carcinogenesis. Here, we demonstrate the carcinogen specificity of this event and its effect on lung tumor evolution. LOH on chromosome 12 was observed in 45% of NNK-induced, 59% of VC-induced, 58% of aflatoxin B1 (AFB1)-induced, 14% of N -ethyl- N -nitrosourea (ENU)-induced and 12% of spontaneous lung adenocarcinomas. The frequency of LOH in each of the carcinogen-induced groups, except ENU, was significantly higher than in the spontaneous group ( P
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high frequency of k ras mutations in spontaneous and Vinyl Carbamate induced lung tumors of relatively resistant b6cf1 c57bl 6j balb cj mice
Carcinogenesis, 1995Co-Authors: Thomas E Massey, Julie F Foley, Robert R Maronpot, Theodora R Devereux, Marshall W AndersonAbstract:The murine K-ras proto-oncogene is hypothesized to be a pulmonary adenoma susceptibility gene. This postulate is supported by the previous demonstration of a preference for mutation of the K-ras allele from the susceptible parent in lung tumors of A/J×C3H F1 mice. We have examinedK-ras activation in control and Vinyl Carbamate (VC) (single dose 0.03 μmol/kg i.p.) treated B6CF1 mice, the progeny of resistant C57BL/6J and intermediately sensitive BALB/cJ parents. Thirty-four of 37 tumors from VC-treated mice and 17 of 23 from controls contained activating K-ras mutations. The spectra of mutations in codons 12 and 61 of K-ras were similar for the two groups, except that 7 tumors from VC-treated mice had A→T transversions in the second base of codon 61; none were observed in tumors from saline-treated animals. PCR-based genotyping of first exon K-ras mutations revealed that the vast majority (15 of 18) of the mutations were in the BALB/cJ allele. Furthermore, the three tumors with mutated C57BL/6J K-ras were among the smallest tumors analyzed. These results are consistent with previous findings in other mouse hybrids showing parental bias for K-ras mutations and suggest that mutation of the allele of the susceptible parent may provide a growth advantage to the tumor
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High frequency of K-ras mutations in spontaneous and Vinyl Carbamate-induced lung tumors of relatively resistant B6CF1 (C57BL/6J×BALB/cJ) mice
Carcinogenesis, 1995Co-Authors: Thomas E Massey, Julie F Foley, Robert R Maronpot, Theodora R Devereux, Marshall W AndersonAbstract:The murine K-ras proto-oncogene is hypothesized to be a pulmonary adenoma susceptibility gene. This postulate is supported by the previous demonstration of a preference for mutation of the K-ras allele from the susceptible parent in lung tumors of A/J×C3H F1 mice. We have examinedK-ras activation in control and Vinyl Carbamate (VC) (single dose 0.03 μmol/kg i.p.) treated B6CF1 mice, the progeny of resistant C57BL/6J and intermediately sensitive BALB/cJ parents. Thirty-four of 37 tumors from VC-treated mice and 17 of 23 from controls contained activating K-ras mutations. The spectra of mutations in codons 12 and 61 of K-ras were similar for the two groups, except that 7 tumors from VC-treated mice had A→T transversions in the second base of codon 61; none were observed in tumors from saline-treated animals. PCR-based genotyping of first exon K-ras mutations revealed that the vast majority (15 of 18) of the mutations were in the BALB/cJ allele. Furthermore, the three tumors with mutated C57BL/6J K-ras were among the smallest tumors analyzed. These results are consistent with previous findings in other mouse hybrids showing parental bias for K-ras mutations and suggest that mutation of the allele of the susceptible parent may provide a growth advantage to the tumor
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Proliferative Lesions of the Mouse Lung: Progression Studies in Strain A Mice
Experimental Lung Research, 1991Co-Authors: Julie F Foley, Gary D Stoner, Jerry F Hardisty, Marshall W Anderson, Beth W. Gaul, Robert R MaronpotAbstract:The progression of pulmonary neoplasia was examined in strain A/J male mice treated with a single dose of Vinyl Carbamate (60 mg/kg, i.p.) 6 weeks after birth. Interim sacrifices were performed at 7, 8, 10, 12, or 14 months. Proliferative lesions of the lung were divided into four categories: hyperplasias, adenomas, carcinomas arising within adenomas, and carcinomas. Grossly visible surface tumor counts, histologic diagnoses, and morphometric measurements of histologic lesions were used to evaluate progression. Vinyl Carbamate-treated mice showed increased mean surface tumor counts at all time points. Diagnostic evaluation suggested that as a function of time, the relative frequency of hyperplasias decreased and the relative frequency of adenomas increased. The relative frequency of adenomas subsequently decreased, whereas the relative frequency of carcinomas increased. At all time points, carcinomas arising within adenomas were present. As time progressed, the number of carcinomas arising within adenomas...
