Analytical data is presented for the occurrence of the three major volatile N-nitrosamines in cigarette tobacco and mainstream smoke, namely N-nitrosodimethylamine (NDMA),- N-nitrosoethylmethylamine (NEMA) and N-nitrosopyrrolidine (NPYR) as well as for the occurrence of the corresponding precursor amines and non-volatile N-nitrosamino acids in tobacco. Experimental studies using the C20 reference cigarette show that NPYR present in mainstream smoke results from direct transfer of preformed NPYR (ca. 1.5%), decarboxylation of N-nitrosoproline in tobacco (ca. 10%), pyrolytic nitrosation of pyrrolidine in tobacco (ca. 37%) and concerted decarboxylation/nitrosation of proline (ca. 52%) during tobacco pyrolysis.

Chromatography, Gas↗

PubMedDate not supplied

Carcinogenic N-nitrosamines in the diet: occurrence, formation, mechanisms and carcinogenic potential.

Nitrosamines form a large group of genotoxic chemical carcinogens which occur in the human diet and other environmental media, and can be formed endogenously in the human body. N-Nitroso compounds can induce cancer in experimental animals. Some representative compounds of this class induce cancer in at least 40 different animal species including higher primates. Tumours induced in experimental animals resemble their human counterparts with respect to both morphological and biochemical properties. Extensive experimental, and some epidemiological data suggest that humans are susceptible to carcinogenesis by N-nitroso compounds and that the presence of these compounds in some foods may be regarded as an aetiological risk factor for certain human cancers including cancers of the oesophagus, stomach and nasopharynx.

Animals↗

PubMedDate not supplied

Detection of mutations in bacteria and of DNA damage and amplified DNA sequences in mammalian cells as a systematic test strategy for elucidating biological activities of chemical carcinogens.

The interdisciplinary evaluation of risks from carcinogens utilizes, inter alia, data on the activities of the compounds in short-term assays. A systematic approach is being used to determine mutagenesis in bacteria (the study of direct activities and specific modes of metabolic activation), DNA damage within primary mammalian cells (DNA single-strand breaks and persistence of damage, by a method extendable to the in vivo situation) and amplified DNA sequences in cultured cells (as an endpoint probably relevant to carcinogenesis). This test combination was expected to reduce some of the shortcomings of other batteries of tests, which suffer from a lack of appropriate metabolic conversion of compounds, irrelevancy of genetic endpoints and pharmacokinetic limitations. Furthermore, as each assay in the test strategy differs from the others only by one of the parameters described above, a reasonable understanding of divergent test results from assay to assay was anticipated. Several substances were investigated to elucidate why their activities in short-term assays and in carcinogenesis experiments do not correlate. The substances were N-nitrodimethylamine, for which formaldehyde is the reactive intermediate in bacterial mutagenesis but not in mammalian cells or in vivo, N-nitrosodiethanolamine, a carcinogen that must be activated by external alcohol dehydrogenase to be mutagenic in bacteria, N-nitrosodialkylamines, with unique organotropism in vivo for which organ-specific activation was studied in vitro, N-nitroso compounds that are inactivated in vivo but not in vitro, and components of the aristolochic acid mixture which may be metabolized oxidatively or reductively, as well as numerous miscellaneous compounds that were expected to be genotoxins on account of their chemical structure. In addition to the assessment of genotoxicity, the results obtained in individual tests of this strategy yield important data on mechanisms of activity, such as organ-specific activation and deactivation, species variations, in vitro/in vivo correlation and persistence or repair of damage.

Animals↗

PubMedDate not supplied

The occurrence of N-nitrosocompounds [corrected] in zarda tobacco.

The levels of tobacco-specific nitrosamines (TSNA), N-nitrosodiethanolamine, volatile and non-volatile N-nitroso compounds in zarda, a partially fermented Indian tobacco product are presented. Total identified N-nitroso compound concentrations ranged from 1.6 to 240 mg/kg fresh weight tobacco, TSNA accounted for 76-91% of the total N-nitroso compound burden. Preformed N-nitrosoethylmethylamine as well as the non-volatile compounds N-nitrososarcosine, N-nitrosoazetidine-4-carboxylic acid and N-nitrosothiazolidine-4-carboxylic acid were identified for the first time in tobacco products. The high levels of N-nitroso compounds present in zarda tobacco indicate that zarda chewing communities are exposed to a considerable exogenic burden of potentially carcinogenic compounds, in particular TSNA.

Carcinogens↗

PubMedDate not supplied

Caffeine-derived N-nitroso compounds. II. Synthesis and characterization of nitrosation products from caffeidine and caffeidine acid.

Caffeine on alkaline hydrolysis produces caffeidine [1-methyl-4-(methylamino)-5-(N-methylcarbamoyl)imidazole] and caffeidine acid [N-[4-(5-carboxy-1-methylimidazolyl)]-N,N'-dimethylurea]. We now report the synthesis and chemical characterization of mononitrosocaffeidine [1-methyl-4-(N-methyl-N-nitrosoamino)-5-(N-methylcarbamoyl)i midazole], dinitroso-caffeidine [1-methyl-4-(N-methyl-N-nitrosoamino)-5-(N-methyl-N-nitrosocarb amo yl) imidazole], and mononitrosamidocaffeidine [1-methyl-4-(methylamino)-5-(N-methyl-N-nitrosocarbamoyl)-Imidazole] based on spectral analysis. The characterization of nitrosated byproducts obtained during the synthesis of these compounds is also presented. Caffeidine is shown to undergo rapid nitrosation in acidic medium to form mononitrosocaffeidine (MNC), an asymmetric N-nitrosamine, and dinitrosocaffeidine (DNC), a N-nitrosamide. Although the reaction proceeds with preferential nitrosation of the amino group in caffeidine, the results also support partial involvement of a mononitrosamide intermediate in the formation of MNC and DNC through transnitrosation of the amino group. The stability data suggest that the nitroso group at the amino nitrogen in DNC influences the reactivity of amide nitroso group. The presence of a trisubstituted ureide moiety in caffeidine acid has been confirmed by NMR nuclear Overhauser effect experiments. Nitrosation of caffeidine acid under acidic conditions produced N,N'-dimethylparabanic acid (DMPA, N,N'-dimethylimidazolidinetrione) as a major product with low amounts of mononitrosocaffeidine and N,N'-dimethyl-N-nitrosourea, whereas nitrosation with NOBF4/pyridine in aprotic medium gave rise to an anhydride, 1,4-dimethyl-4,5-dihydro-5,7-dioxo-1H,7H-imidazo[4,5-d][1,3]oxazine. The nitrosation of methyl ester of caffeidine acid resulted in the formation of a N-nitrosourea derivative, N-[4-(5-carboxy-1-methylimidazolyl)]-N'-nitroso-N,N'-dimethylurea. (ABSTRACT TRUNCATED AT 250 WORDS)

Caffeine↗

PubMedDate not supplied

The nitrosation of hexetidine and hexedine: characterization of the major nitrosamine from common antimicrobial agents.

The acidic nitrosation of hexetidine and hexedine, common antimicrobial agents and drug constituents, leads to a mixture of nitrosamines. The major nitrosamine product, "HEXNO", forms rapidly in yields as high as 60% over the pH range 1-4.8 at incubation times of 1 h at 37 degrees C with 40 mM NO2- and 10 mM hexetidine. On the basis of extensive spectroscopic characterization and independent synthesis HEXNO has been assigned the structure of 1-(2-ethylhexyl)-3-nitroso-4-methyl-4-[[N-(2-ethylhexyl)-N- nitrosoamino]methyl]imidazolidine (7). The synthesis of HEXNO involves the novel interception by potassium nitrite in ether/18-crown-6 of an imminium ion produced from the reaction of hexedine with benzyl chloroformate. Collapse of the alpha-amino nitrous ester produced by this reaction yields the nitrosamine containing carbamate 8, which yields HEXNO after removal of the carbamate with trimethylsilyl iodide and subsequent nitrosation. The rapid formation of HEXNO from hexetidine and hexedine supports the hypothesis that tertiary geminal diamines will produce nitrosamines rapidly by a mechanism which involves the cleavage of a nitrosammonium ion with the assistance of the neighboring nitrogen atom. This process is deemed to be of possible importance in the endogenous production of potentially carcinogenic nitrosamines because of its low nitrite requirement and high nitrosation rate. The available data suggest the probable formation of HEXNO and other nitrosamines from hexetidine under conditions of its use.

Chromatography, High Pressure Liquid↗