10 research outputs found

    DNA methylation in rat stomach and duodenum following chronic exposure to N-methyl-N′-nitro-N-nitrosoguanidine and the effect of dietary taurocholate

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    N-Methyl-N′-nitro-N-nitrosoguanidine (MNNG) induces a high incidence of carcinomas in the glandular stomach of rats following chronic administration in the drinking water. We determined the level of 7-methylguanine and O6-mehtylguanine in gastric and duodenal DNA during chronic exposure to MNNG (80 p.p.m.). After considerable fluctuations during the initial 3 weeks, levels of methylpurines reached a steady state which was approximately three times higher in the pylorus (i.e. the preferential site of tumor induction)than in the fundus and duodenum, with 7-methylguanine and O6-methylguanine values in the rangeof 520 and 110 μmol/mol guanine, respectively. When rats were given MNNG in the drinking water at concentrations ranging from 10 to 80 p.p.m. for 3 weeks, levels of methylpurines reached maximum values already at 10-20 p.p.m. At higher MNNG concentrations, there was no further increase in DNA alkylation. The reason for this lack of dose response remained unclear. Immunohistochemical analyses showed that DNA methylatlon by MNNG is restricted to epithelial cells bordering the luminal surface. The possibility exists that in this target cell population the content of free thiols is a limiting factor for the decomposition of MNNG and its reaction with macromolecules in the gastric mucosa. Addition to the diet of sodium taurocholate, a bile acid previously shown to enhance MNNG-induced stomach carcinogenesis, did not influence the extent of DNA methylation, indicating that it acts as a promote

    European regulations on the use of antibiotics in veterinary medicine

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    Antimicrobial resistance endangers the successful combat of bacterial infections in humans and animals. The common use of antibiotic classes including those of high clinical value in human as well as veterinary medicine is a critical factor contributing to or suspected to promote the emergence of antibiotic resistance. New legal provisions laid down in veterinary drug legislations and related guidelines and advice are in force in the European Union to safeguard the effectiveness, accessibility and availability of antibiotics. Categorisation of antibiotics in classes of importance for treatment of infections of humans by the WHO was one of the first steps. This task is also undertaken for antibiotics for treatment of animals by the EMA's Antimicrobial Advice Ad Hoc Expert Group. The new veterinary Regulation (EU) 2019/6 has extended restrictions for use of some antibiotics in animals to a full ban of certain antibiotics. While some (but not all) antibiotic compounds not being authorized in veterinary medicine may still be used in companion animals more strict provisions were already applicable for treatment of food producing animal species. Distinct regulations are in place for the treatment of animals kept in large numbers in flocks. Initial regulations focussed on the protection of consumers from residues of veterinary drugs in food commodities, new regulations address prudent (not routinely) and responsible selection, prescription and use of antibiotics, and have improved the practicality for cascade use outside the terms of marketing authorisation. Mandatory recording of use of veterinary medicinal products for food safety reasons is extended to rules for veterinarians and owners or holders of animals to regularly report the use of antibiotics for the purpose of official surveillance of consumption. National sales data of antibiotic veterinary medicinal products have been collected on a voluntary basis until 2022 by ESVAC, which has created awareness of major differences between EU member states. A significant decline in sales was reported for third and fourth generation cephalosporines, polymyxins (colistin), and (fluoro)quinolones since the initiation in 2011

    Nafenopin-induced rat liver peroxisome proliferation reduces DNA methylation by N-nitrosodimethylamine in vivo

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    The hypolipidaemic drug nafenopin (NAF) has been shown to enhance the hepatocarcinogenic effect of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine in rats. We have investigated whether the NAF-induced peroxisome proliferation in hepatocytes interferes with NDMA's metabolism and interaction with DNA. Adult male Wistar rats received a single i.p. injection of [14C]NDMA (2 mg/kg) and were killed 4 h later. DNA was isolated from liver and kidney, hydrolysed in 0.1 N HCI and analysed by Sephasorb chromatography. In rats pre-treated with NAF (0.2% in the diet over a period of 3 weeks), the concentration of N7-methylguanine in hepatic DNA (μmol/mol guanine) was 46% below control values. This is probably due to the greater amount of target DNA, as NAF caused a marked hepatomegaly with a 50% increase in total liver DNA content. Concentrations of N7-methylguanine in kidney DNA were twice as high in NAF-pre-treated animals when compared to control rats. This is unlikely to result from a shift in the metabolism of NDMA from liver to other rat tissues since the time course and extent of the conversion of [14C]NDMA to 14CO2 and 14C-labelled urinary metabolites were identical in NAF-treated and control animals. There was no indication that NAF inhibits the activity of the hepatic O6-alkylguanine-DNA alkyltransferas

    DNA methylation in rat tissues by a series of homologous aliphatic nitrosamines ranging from N-nitrosodimethylamine to N-nitrosomethyldodecylamine

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    Aliphatic N-nitrosomethylalkylamines exhibit a remarkable organ specificity in rats, the principal targets for tumour induction being liver, oesophagus, urinary bladder and lung. We have determined the extent of DNA methylation in these tissues following a single oral dose (0.1 mmol/kg; 6 h survival) of each of 12 homologues, ranging from N-nitrosodimethylamine (C1) to N-nitrosomethyldodecylamine (C12). Methylpurines (7-and O6-methylguanine) were determined by cation exchange HPLC with fluorescence detection. Highest levels of hepatic DNA methylation were found with N-nitrosodimethylamine (C1) and N-nitrosomethylethylamine (C2), the most potent hepatocarcinogens in this series. Concentrations of methylpurines in liver DNA decreased with increasing chain length for C1-C5. Administration of the higher homologues (C6-C12) caused levels of DNA methylation which by themselves were considered too low to account for their hepatocarcinogenicity. In rat oesophagus, DNA methylation closely paralleled carcinogenicity, the butyl and pentyl derivatives (C4, C5) being most effective. In rat lung, the extent of DNA methylation was generally lower and there was no apparent correlation with carcinogenicity. Methylation of kidney DNA also decreased with increasing chain length and was only detectable for C1-C5. In urinary bladder DNA, methylpurines were below or close to the limit of detection. It is concluded that the initiation of malignant transformation by DNA methylation alone (through hydroxylation at the methylene α-carbon) could be operative for Cl in kidney and lung, for Cl and C2 in liver, and C3-C5 in oesophagus. For the higher homologues, the extent of DNA methylation seems insufficient to explain the complex pattern of tissue specificity, suggesting that DNA modification other than, or in addition to, methylation may be responsibl

    Chemical characterization by GC-MS and in vitro activity against Candida albicans of volatile fractions prepared from Artemisia dracunculus, Artemisia abrotanum, Artemisia absinthium and Artemisia vulgaris

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    BACKGROUND: A large number of essential oils is reported to have significant activity against Candida albicans. But the different chemical composition influences the degree of their activity. The intention of this study was to investigate the chemical composition and the activity against Candida albicans of volatile oils obtained from Artemisia dracunculus, A. abrotanum, A. absinthium and A. vulgaris (Asteraceae). The aim of the study was to identify new chemical compounds that have effect against C. albicans. The essential oils were obtained by hydrodistillation or extraction with dichloromethane (a new procedure we developed trying to obtain better, more separated compounds) from air dried above ground plant material and analyzed by GC-MS. Additionally commercial essential oils from the same species were tested. The Candida albicans inhibition studies were carried out by the paper disc diffusion method. RESULTS: The essential oils shared common components but presented differences in composition and showed variable antifungal activity. Davanone and derivatives thereof, compounds with silphiperfolane skeleton, estragole, davanone oil, β-thujone, sabinyl acetate, herniarin, cis-chrysanthenyl acetate, 1,8-cineol, and terpineol were the main components of Artemisia volatiles. CONCLUSIONS: Among the volatile fractions tested those from A. abrotanum containing davanone or silphiperfolane derivatives showed the highest antifungal activity. The in vitro tests revealed that the Artemisia oils are promising candidates for further research to develop novel anti-candida drugs

    β-Deuteration of N-nitrosoethylmethylamine causes a shift in DNA methylation from rat liver to esophagus

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    While N-nitrosoethylmethylamine (NEMA) is carcinogenic primarily for the liver, its β-trideuterated derivative, N-nitroso([2-D3]ethyl)methylamine (NEMA-d3), also produces a high incidence of tumors in the esophagus. To determine whether this shift in organ specificity is associated with an altered pattern of DNA alkylation, [methyl-14C]- and [1-ethyl-14C]-labeled NEMA-d3 were administered to adult male Fischer 344 rats as a single i.p. dose (0.05 mmol/kg; 4 h survival). Levels of methylated and ethylated purines in the DNA of various organs were determined by radiochromatography on Sephasorb-HP columns. When compared to previous data using undeuterated NEMA, 7-niethylguanine levelswerefoundtobereducedby ∽30%inliverandkldney, but were 160% greater in esophagus. This resulted in a decrease in the 7-methylguanine ratio for liver/esophagus from 109 to 29. O6-Methlguanine was diminished in liver and kidney, but levels in lung and esophagus were too low for quantitative detection. Similarly, deuteration led to an 18% decrease of 7-ethylguanine In hepatic DNA. The observed increase in esophageal DNA methylation correlates with the increased carcinogenicity of NEMA-d3 relative to undeuterated NEMA in that organ. Since pharmacokinetic studies have shown that β-trideuteration of NEMA does not alter its bioavailability, the data suggest that the observed shift in target organ results from isotopically-induced changes in the balance among competing metabolic pathways in different rat tissue

    DNA methylation in rat stomach and duodenum following chronic exposure to N-methyl-N′-nitro-N-nitrosoguanidine and the effect of dietary taurocholate

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    N-Methyl-N′-nitro-N-nitrosoguanidine (MNNG) induces a high incidence of carcinomas in the glandular stomach of rats following chronic administration in the drinking water. We determined the level of 7-methylguanine and O6-mehtylguanine in gastric and duodenal DNA during chronic exposure to MNNG (80 p.p.m.). After considerable fluctuations during the initial 3 weeks, levels of methylpurines reached a steady state which was approximately three times higher in the pylorus (i.e. the preferential site of tumor induction)than in the fundus and duodenum, with 7-methylguanine and O6-methylguanine values in the rangeof 520 and 110 μmol/mol guanine, respectively. When rats were given MNNG in the drinking water at concentrations ranging from 10 to 80 p.p.m. for 3 weeks, levels of methylpurines reached maximum values already at 10-20 p.p.m. At higher MNNG concentrations, there was no further increase in DNA alkylation. The reason for this lack of dose response remained unclear. Immunohistochemical analyses showed that DNA methylatlon by MNNG is restricted to epithelial cells bordering the luminal surface. The possibility exists that in this target cell population the content of free thiols is a limiting factor for the decomposition of MNNG and its reaction with macromolecules in the gastric mucosa. Addition to the diet of sodium taurocholate, a bile acid previously shown to enhance MNNG-induced stomach carcinogenesis, did not influence the extent of DNA methylation, indicating that it acts as a promote

    DNA methylation in rat tissues by a series of homologous aliphatic nitrosamines ranging from N-nitrosodimethylamine to N-nitrosomethyldodecylamine

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    Aliphatic N-nitrosomethylalkylamines exhibit a remarkable organ specificity in rats, the principal targets for tumour induction being liver, oesophagus, urinary bladder and lung. We have determined the extent of DNA methylation in these tissues following a single oral dose (0.1 mmol/kg; 6 h survival) of each of 12 homologues, ranging from N-nitrosodimethylamine (C1) to N-nitrosomethyldodecylamine (C12). Methylpurines (7-and O6-methylguanine) were determined by cation exchange HPLC with fluorescence detection. Highest levels of hepatic DNA methylation were found with N-nitrosodimethylamine (C1) and N-nitrosomethylethylamine (C2), the most potent hepatocarcinogens in this series. Concentrations of methylpurines in liver DNA decreased with increasing chain length for C1-C5. Administration of the higher homologues (C6-C12) caused levels of DNA methylation which by themselves were considered too low to account for their hepatocarcinogenicity. In rat oesophagus, DNA methylation closely paralleled carcinogenicity, the butyl and pentyl derivatives (C4, C5) being most effective. In rat lung, the extent of DNA methylation was generally lower and there was no apparent correlation with carcinogenicity. Methylation of kidney DNA also decreased with increasing chain length and was only detectable for C1-C5. In urinary bladder DNA, methylpurines were below or close to the limit of detection. It is concluded that the initiation of malignant transformation by DNA methylation alone (through hydroxylation at the methylene α-carbon) could be operative for Cl in kidney and lung, for Cl and C2 in liver, and C3-C5 in oesophagus. For the higher homologues, the extent of DNA methylation seems insufficient to explain the complex pattern of tissue specificity, suggesting that DNA modification other than, or in addition to, methylation may be responsibl

    β-Deuteration of N-nitrosoethylmethylamine causes a shift in DNA methylation from rat liver to esophagus

    Full text link
    While N-nitrosoethylmethylamine (NEMA) is carcinogenic primarily for the liver, its β-trideuterated derivative, N-nitroso([2-D3]ethyl)methylamine (NEMA-d3), also produces a high incidence of tumors in the esophagus. To determine whether this shift in organ specificity is associated with an altered pattern of DNA alkylation, [methyl-14C]- and [1-ethyl-14C]-labeled NEMA-d3 were administered to adult male Fischer 344 rats as a single i.p. dose (0.05 mmol/kg; 4 h survival). Levels of methylated and ethylated purines in the DNA of various organs were determined by radiochromatography on Sephasorb-HP columns. When compared to previous data using undeuterated NEMA, 7-niethylguanine levelswerefoundtobereducedby ∽30%inliverandkldney, but were 160% greater in esophagus. This resulted in a decrease in the 7-methylguanine ratio for liver/esophagus from 109 to 29. O6-Methlguanine was diminished in liver and kidney, but levels in lung and esophagus were too low for quantitative detection. Similarly, deuteration led to an 18% decrease of 7-ethylguanine In hepatic DNA. The observed increase in esophageal DNA methylation correlates with the increased carcinogenicity of NEMA-d3 relative to undeuterated NEMA in that organ. Since pharmacokinetic studies have shown that β-trideuteration of NEMA does not alter its bioavailability, the data suggest that the observed shift in target organ results from isotopically-induced changes in the balance among competing metabolic pathways in different rat tissue
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