Carcinogenic semicarbazide induces sequence-specific DNA damage through the generation of reactive oxygen species and the derived organic radicals
Mie University, Tu, Mie, JapanMutation Research/Fundamental and Molecular Mechanisms of Mutagenesis (Impact Factor: 3.68). 05/2003; 536(1-2):91-101. DOI: 10.1016/S1383-5718(03)00030-5
Semicarbazide, a hydrazine derivative, is carcinogenic to mice but shows no or little mutagenicity in the Salmonella-microsome test. To clarify whether or not the genotoxic mechanism contributes to the non-mutagenic carcinogenicity of semicarbazide, we investigated DNA damage induced by semicarbazide using 32P-5'-end-labeled DNA fragments obtained from the c-Ha-ras-1 protooncogene and the p53 tumor suppressor gene. Semicarbazide caused DNA damage frequently at the thymine and cytosine residues in the presence of Cu(II). Catalase and bathocuproine partially inhibited DNA damage, suggesting that hydrogen peroxide plus Cu(I) participates in DNA damage. When a high concentration of semicarbazide was used in the presence of catalase, DNA damage was induced, especially at G in 5'-AG and slightly at 5'-G in GG and GGG sequences. An electron paramagnetic resonance (EPR) spectroscopic study has confirmed that the reaction of semicarbazide with Cu(II) produces carbamoyl radicals (z.rad;CONH(2)), possibly generated via the nitrogen-centered radicals of semicarbazide. Azodicarbonamide also produced carbamoyl radicals and induced DNA damage frequently at 5'-G in GG and GGG sequences, suggesting that carbamoyl radicals participate in this sequence-specific DNA damage by semicarbazide. On the basis of our previous reports, we consider that the sequence-specific DNA damage at G in 5'-AG in the present study is due to the nitrogen-centered radicals. This study has shown that semicarbazide induces DNA damage in the presence of Cu(II) through the formation of hydrogen peroxide and Cu(I). In addition, semicarbazide-derived free radicals participate in DNA damage. DNA damage induced by these reactive species may be relevant to the carcinogenicity of semicarbazide.
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ABSTRACT: Contaminants are a vast subject area of food safety and quality. They are generally divided into chemical, microbiological and physical classes and are present in our food chain from raw materials to finished products. They are the subject of international and national legislation that has widened to cover more and more contaminant classes and food categories. In addition, consumers have become increasingly aware of and alarmed by their risks, whether rightly or not. What is the food industry doing to ensure the safety and quality of the products we feed our children? This is a valid question which this article attempts to address from an industrial viewpoint. Chemical food safety is considered a complex field where the risk perception of consumers is often the highest. The effects of chronic or acute exposure to chemical carcinogens may cause disease conditions long after exposure that can be permanently debilitating or even fatal. It is also a moving target, as knowledge about the toxicity and occurrence data of new chemical contaminants continues to be generated. Their identification, prevention and management are challenges to the food industry as a whole. A reminder of the known chemical hazards in the food chain will be presented with an emphasis on the use of early warning to identify potential new contaminants. Early warning is also a means of prevention, anticipating food safety concerns before they become issues to manage. Current best management practices including Hazard Analysis and Critical Control Points relating to the supply chain of baby foods and infant formulae will be developed. Finally, key lessons from a case study on recent contamination issues in baby food products will be presented.01/2007; 60:65-78. DOI:10.1159/000106361
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ABSTRACT: Procarbazine [N-isopropyl-alpha-(2-methylhydrazino)-p-toluamide], a hydrazine derivative, which has been shown to have effective antineoplastic activity, induces cancer in some experimental animals and humans. To clarify a new mechanism for its carcinogenic effect, we examined DNA damage induced by procarbazine in the presence of metal ion, using 32P-5'-end-labeled DNA fragments obtained from the human p53 tumor suppressor gene and the c-Ha-ras-1 protooncogene. Procarbazine plus Cu(II) induced piperidine-labile and formamidopyrimidine-DNA glycosylase-sensitive lesions at the 5'-ACG-3' sequence, complementary to a hotspot of the p53 gene, and the 5'-TG-3' sequence. Catalase partially inhibited DNA damage, suggesting that not only H(2)O(2) but also other reactive species are involved. Procarbazine plus Cu(II) significantly increased the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine, which was completely inhibited by calatase. Electron spin resonance spin-trapping experiments revealed that methyl radicals were generated from procarbazine and Cu(II). On the basis of these findings, it is considered that procarbazine causes DNA damage through non-enzymatic formation of the Cu(I)-hydroperoxo complex and methyl radicals. In conclusion, in addition to alkylation, oxidative DNA damage may play important roles in not only antitumor effects but also mutagenesis and carcinogenesis induced by procarbazine.Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 09/2003; 539(1-2):145-55. DOI:10.1016/S1383-5718(03)00157-8 · 3.68 Impact Factor
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ABSTRACT: Nitrofuran antibiotics were previously used in animal healthcare but are now prohibited. Semicarbazide is a breakdown product of 5-nitrofurazone and protein-bound semicarbazide is used as a marker residue for the illegal use of 5-nitrofurazone. However, the presence of the prohibited semicarbazide has been reported in some food items of animal origin. A novel observation is reported that semicarbazide can be detected in Finnish crayfish samples, i.e. crustacea, never medicated with nitrofurazone. The origin of the semicarbazide is presently unknown. Positive identification was undertaken by liquid chromatography coupled with tandem mass spectrometry detection. The level of semicarbazide was determined as the protein-bound form as well as the total amount of semicarbazide in the sample. The average levels of total semicarbazide and the protein-bound form were 4.2 and 0.5 ng g(-1) fresh crayfish meat, respectively. All the tested samples (n = 18) contained traces of semicarbazide, the highest amount being 12 ng g(-1) fresh crayfish meat.Food Additives and Contaminants 10/2004; 21(9):825-32. DOI:10.1080/02652030400002329 · 2.13 Impact Factor
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