Carcinogenicity Of N-nitroso Compounds Research Articles

Lack of the DNA repair protein O6-methylguanine-DNA methyltransferase in histologically normal brain adjacent to primary human brain tumors.

Exposure to exogenous alkylating agents, particularly N-nitroso compounds, has been associated with increased incidence of primary human brain tumors, while intrinsic risk factors are currently unknown. The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is a major defense against the carcinogenicity of N-nitroso compounds and other alkylators. We report here that in 55% (64/117) of cases, histologically normal brain tissue adjacent to primary human brain tumors lacked detectable MGMT activity [methyl excision repair-defective (Mer-) status]. The incidence of Mer- status in normal brain tissue from brain tumor patients was age-dependent, increasing from 21% in children 0.25-19 years of age to 75% in adults over 50. In contrast, Mer- status was found in 12% (5/43) of normal brain specimens from patients operated for conditions other than primary brain tumors and was not age-dependent. The 4.6-fold elevation in incidence of Mer- status in brain tumor patients is highly significant (chi2 = 24; p < or = 0.001). MGMT activity was independent of age in the lymphocytes of brain tumor patients and was present in lymphocytes from six of nine tumor patients whose normal brain specimen was Mer-. DNA polymerase beta, apurinic/apyrimidinic endonuclease, and lactate dehydrogenase activities were present in all specimens tested, including Mer- specimens from brain tumor patients. Our data are consistent with a model of carcinogenesis in human brain in which epigenetically regulated lack of MGMT is a predisposing factor and alkylation-related mutagenesis is a driving force.

Nitrates, nitrites andN‐nitrosocompounds: A review of the occurrence in food and diet and the toxicological implications

Data on occurrence of nitrate, nitrite and N-nitrosocompounds in food and drinking water, and on total dietary intakes are reviewed. Metabolic, toxicological and epidemiological studies are surveyed and the implications with respect to safety evaluation are addressed. It is concluded that, on the basis of recent long-term animal studies and of clinical experience in man, the current Acceptable Daily Intake (ADI) allocated to nitrate by the Joint FAO/WHO Expert Committee on Food Additives of 0-5 mg/kg body weight/day (expressed as sodium nitrate) might be increased to 0-25 mg/kg body weight/day. Based on similar criteria, the ADI for nitrite would be 0-0.1 mg/kg body weight/day (expressed as sodium nitrite). In view of the known carcinogenicity of N-nitrosocompounds, exposure to these compounds in food should be minimized by appropriate technological means, such as lowering the nitrite concentration in preserved foods to the minimum required to ensure microbiological safety and use of inhibitors of nitrosation like alpha-tocopherol or ascorbic acid. Further work is needed to define the minimal levels of nitrite in foods needed to inhibit outgrowth of Clostridium botulinum and toxin production.

Synthesis and characterization of oligodeoxynucleotides containing 4-O-methylthymine.

The carcinogenicity of N-nitroso compounds is believed to result from the alkylation of DNA, particularly on O-6 of the guanine and O-4 of the thymine residues. In order to study the base-pairing properties of 4-O-methylthymidine (T*) residues and the structural changes produced in DNA by the presence of this alkylated nucleoside, the oligodeoxyribonucleotides T*GCG, CGCAAGCTT*GCG, CGCGAGCTT*GCG, and CGCAAGCTTGCG were synthesized by the phosphotriester approach in solution. The 4-O-methylthymidine required for oligonucleotide synthesis was prepared by treating the 4-(3-nitro-1,2,4-triazolo) derivative of 3',5'-bis-O-(methoxyacetyl)thymidine with 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) in methanol solution. The susceptibility of the 4-O-methyl group of T* toward nucleophiles enables this group of 4-O-methylthymidine-containing oligomers to be labeled by a direct exchange reaction with [13C]- or [14C]methanol in the presence of DBU. Although it has been previously suggested that 4-O-methylthymine forms stable base pairs with guanine, the thermal melting profiles of the double helices formed by these dodecamers suggest that the presence of 4-O-methylthymine paired to either adenine or guanine destablizes the helix. The melting curve of the sequence containing a 4-O-methylthymine residue base paired to guanine was biphasic and similar to that of an analogous sequence containing 6-O-methylguanine paired to thymine.

Animal Species in which N-nitroso compounds induce cancer.

In reviews on the carcinogenicity of N-nitroso compounds (NC) the number of animal species in which these compounds induce cancer is understated. In recent years additional species have been used in experiments. Tumours have been induced by NC in 39 species which belong to 36 genera, 25 families, 17 orders and five class of animals. The names of these taxa are presented in Latin and the common names of species are given in English, French and German. The carcinogenic action of eight NC in various species is tabulated.

The carcinogenicity of N-nitroso compounds: A SIMCA pattern recognition study

A number of methods are available for evaluating the potential of chemical agents to induce cancer in test animals. Recent use of SIMCA pattern recognition in structure-biological activity studies suggests that this method may be useful in making such evaluations. In this report this method is used to estimate the potential of a number of N-nitroso compounds to induce tumors in the rat. The data treatment and estimation results are consistent with the chemistry of these substances.

衛生化学領域におけるN-ニトロソ化合物

A review of N-nitroso compounds which might be formed secondarily in various foods, with references to past literature on the carcinogenicity and mutagenicity of the N-nitroso compounds. Special references are made to recent literature on N-nitroso compounds detected in daily food, distribution of nitrogenous compounds and nitrites which are considered to be precursors, inhibitive and accelerative factors of N-nitrosation reaction, nitrosation of pharmaceuticals and agricultural chemicals, carcinogenicity of N-nitroso compounds, and correlation between food and human cancer.