A study of tobacco carcinogenesis, LIII: carcinogenicity of N′-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in mink (Mustala vison)

Koppang, N.; Rivenson, Abraham; Dahle, Hans Kolbein; Hoffmann, Dietrich

doi:10.1016/s0304-3835(96)04507-7

Cited by 19 publications

(12 citation statements)

References 10 publications

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“…at 4-week intervals for a total of four doses over 4 months so as to minimize the toxicity of NNK. This total dose of NNK (200 mg) used in the ferrets was based on that the mink, receiving a single of dose (150 mg) of tobacco-carcinogen N-nitrosoamine (NNN), did not show any toxic effects [20]. Three ferrets died in the NNK treated group during the experiment period (between 11 – 14 weeks after the first injection of NNK) without any obvious pathology.…”

Section: Resultsmentioning

confidence: 99%

Development of ferret as a human lung cancer model by injecting 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK)

et al. 2013

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Objective Development of new animal lung cancer models that are relevant to human lung carcinogenesis is important for lung cancer research. Previously we have shown the induction of lung tumor in ferrets (Mustela putorius furo) exposed to both tobacco smoke and a tobacco carcinogen (4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone, NNK). In the present study, we investigated whether NNK treatment alone induces both preneoplastic and neoplastic lesions in the lungs of ferrets. Methods We exposed ferrets to NNK by i.p. injection of NNK (50 mg/kg BW) once a month for four consecutive months and then followed up for 24, 26 and 32 weeks. The incidences of pulmonary preneoplastic and neoplastic lesions were assessed by histopathological examination. The expressions of α7 nicotinic acetylcholine receptor (α7 nAChR, which has been shown to promote lung carcinogenesis) and its related molecular biomarkers in lungs were examined by immunohistochemistry and/or Western blotting analysis. Results Ferrets exposed to NNK alone developed both preneoplastic lesions (squamous metaplasia, dysplasia and atypical adenomatous hyperplasia) and tumors (squamous cell carcinoma, adenocarcinoma and adenosquamous carcinoma), which are commonly seen in humans. The incidence of tumor induced by NNK was time-dependent in the ferrets (16.7%, 40.0% and 66.7% for 24, 26 and 32 weeks, respectively). α7 nAChR is highly expressed in the ferret bronchial/bronchiolar epithelial cells, and alveolar macrophages in ferrets exposed to NNK, and in both squamous cell carcinoma and adenocarcinoma of the ferrets. In addition, we observed the tendency for an increase in phospho-ERK and cyclin D1 protein levels (p = 0.081 and 0.080, respectively) in the lungs of ferrets exposed to NNK. Conclusion The development of both preneoplastic and neoplastic lesions in ferret lungs by injecting NNK alone provides a simple and highly relevant non-rodent model for studying biomarkers/molecular targets for the prevention, detection and treatment of lung carcinogenesis in humans.

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Section: Resultsmentioning

confidence: 99%

Development of ferret as a human lung cancer model by injecting 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK)

et al. 2013

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“…NNN and NNK are presented in the rough tobacco, and their quantity rises in the process of preparation of snuff, so that contained in 1.g of snuff is higher than in one cigarette. 2 Both NNN and NNK have been found to be carcinogenic speci cally in the nose in the mink, when applied systemically. Their combined administration has stronger carcinogenic effect, than any of them given alone.…”

Section: Does Dry Snuff Cause Cancer?mentioning

confidence: 99%

“…Smoking is a widely recognized major risk factor for lung cancer, upper aerodigestive tract neoplasms and other malignancies, cardiovascular, gastrointestinal and neurological diseases. [1][2][3][4][5][6] The large majority of smokers are well aware of the devastating effects of this habit on their health and wish to quit. Modern society's intolerance to smoking grows and many different restrictions have been currently imposed on smokers both in the occupational and social environments.…”

Section: Introductionmentioning

confidence: 99%

Nasal snuff: historical review and health related aspects

Sapundzhiev

Werner

2003

J. Laryngol. Otol.

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With cigarette smoking declining in the modern world, the tobacco industry has to look for other products that can keep the old customers and attract new ones. Different forms of smokeless tobacco are currently massively promoted and are gaining in importance. Dry nasal snuff--the oldest known form of tobacco in Europe--is one of them. The health risks associated with it are different to those attributed to smoking and oral wet snuff. The nicotine contained leads to dependency. Its resorption rate is similar to that of smoking, so it could be seen as an adequate substitutional therapy. The risk for cardiovascular diseases is lower, compared to that for smokers. Chronic abuse leads to morphological and functional changes in the nasal mucosa. Although it contains substances that are potentially carcinogenic, at present, there is no firm evidence, relating the use of nasal snuff to a higher incidence of head and neck or other malignancies.

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“…There are two enzyme species responsible for the N-demethylation of dimethylnitrosamine (DMN) through an oxidative N-demethylation reaction, namely DMN-Ndemethylases I and II (which can operate at ~ 4 mM and ~200 mM of DMN respectively) [69,221]. It was found that following the Ndemethylation of dimethylnitrosamine (DMN), a diazonium ion is produced leading ultimately to the formation of carbonium ion that methylates DNA [222][223][224]. It was suggested that the carcinogenic effects of alkylating agents are proportional to the activities of their activating enzymes in the liver [225,226] since more of the active metabolites might be produced [226], when the demethylases are activated.…”

Section: Bioactivatlon Of N-nitroso Compoundsmentioning

confidence: 99%

Drug-Metabolizing Enzymes Mechanisms and Functions

Sheweita

2000

CDM

213

128

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Drug-metabolizing enzymes are called mixed-function oxidase or monooxygenase and containing many enzymes including cytochrome P450, cytochrome b5, and NADPH-cytochrome P450 reductase and other components. The hepatic cytochrome P450s (Cyp) are a multigene family of enzymes that play a critical role in the metabolism of many drugs and xenobiotics with each cytochrome isozyme responding differently to exogenous chemicals in terms of its induction and inhibition. For example, Cyp 1A1 is particularly active towards polycyclic aromatic hydrocarbons (PAHs), activating them into reactive intermediates those covalently bind to DNA, a key event in the initiation of carcinogenesis. Likewise, Cyp 1A2 activates a variety of bladder carcinogens, such as aromatic amines and amides. Also, some forms of cytochrome P450 isozymes such as Cyp 3A and 2E1 activate the naturally occurring carcinogens (e.g. aflatoxin B1) and N-nitrosamines respectively into highly mutagenic and carcinogenic agents. The carcinogenic potency of PAHs, and other carcinogens and the extent of binding of their ultimate metabolites to DNA and proteins are correlated with the induction of cytochrome P450 isozymes. Phase II drug-metabolizing enzymes such as glutathione S-transferase, aryl sulfatase and UDP-glucuronyl transferase inactivate chemical carcinogens into less toxic or inactive metabolites. Many drugs change the rate of activation or detoxification of carcinogens by changing the activities of phases I and II drug-metabolizing enzymes. The balance of detoxification and activation reactions depends on the chemical structure of the agents, and is subjected to many variables that are a function of this structure, or genetic background, sex, endocrine status, age, diet, and the presence of other chemicals. It is important to realize that the enzymes involved in carcinogen metabolism are also involved in the metabolism of a variety of substrates, and thus the introduction of specific xenobiotics may change the operating level and the existence of other chemicals. The mechanisms of modification of drug-metabolizing enzyme activities and their role in the activation and detoxification of xenobiotics and carcinogens have been discussed in the text.

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A study of tobacco carcinogenesis, LIII: carcinogenicity of N′-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in mink (Mustala vison)

Cited by 19 publications

References 10 publications

Development of ferret as a human lung cancer model by injecting 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK)

Development of ferret as a human lung cancer model by injecting 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK)

Nasal snuff: historical review and health related aspects

Drug-Metabolizing Enzymes Mechanisms and Functions

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