Systemic genotoxic effects of tobacco-related nitrosamines following oral and inhalational administration to Sprague-Dawley rats
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Summary
An ex vivo model to detect nonspecific DNA damage in different rat tissues has been developed and employed to study systemic properties of tobacco-specific N-nitrosamines. One hour after treatment of rats with the carcinogens, primary, intact cells were isolated from various organs. Viability of the cells was monitored by trypan blue exclusion. Genotoxicity was determined by alkaline elution, in situ nick translation or microgel electrophoresis. We found that oral application of 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces genotoxic effects in the liver (3.125–50 mg/kg), whereas N-nitrosonornicotine (NNN) is only moderately active (50–100 mg/kg). Furthermore, oral administration of NNK, NNN, and of N-nitrosodimethylamine (NDMA), induces DNA damage in the nasal cavity. In peripheral blood lymphocytes genotoxicity of NDMA (< 2 mg/kg), but not of NNK (50 mg/kg), was observed. NDMA and NNK are just as genotoxic in the liver when administered by inhalation as orally (effective doses: 0.1–1 and 50 mg/kg, respectively). For human cancer, these results indicate that in addition to the susceptibilities in local organs (oral cavity after snuff dipping and lung after tobacco smoke inhalation), these nitrosamines also pose a risk systemically for more remote organs.
Key words
Tobacco-specific nitrosamines Toxicokinetics Genotoxicity Systemic effects Primary cells Detection of DNA damageAbbreviations
- AE
alkaline filter elution
- ATP
adenosine triphosphate
- C
values obtained for untreated control groups
- CTP
cytidine triphosphate
- DMSO
dimethyl sulphoxide
- GTP
guanosine triphosphate
- MGE
microgel electrophoresis
- NDMA
N-nitrosodimethylamine
- NMBzA
N-nitrosomethylbenzylamine
- NNK
4-(N-methyl-N-nitrosoamino)-1-(3-pyridyl)-1-butanone
- NNN
N-nitrosonornicotine
- NT
nick translation
- T
values obtained for test groups
- TTP
thymidine triphosphate
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