Chemical research in toxicology
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Chem. Res. Toxicol. · Sep 2008
Identification and characterization of thiosemicarbazones with antifungal and antitumor effects: cellular iron chelation mediating cytotoxic activity.
Thiosemicarbazones derived from acetylpyrazines were prepared by condensing an acetylpyrazine or a ring-substituted acetylpyrazine with thiosemicarbazide. Using the same procedure, N, N-dimethylthiosemicarbazones were synthesized from acetylpyrazines and N, N-dimethylthiosemicarbazide. A total of 20 compounds (16 novel) were chemically characterized and then tested for antifungal effects on eight strains of fungi and also for antitumor activity against SK-N-MC neuroepithelioma cells. ⋯ In contrast, compounds 6 and 7 that do not possess a tridentate metal-binding site showed little activity. Further studies examining ascorbate oxidation demonstrated that the Fe complexes of the most effective compounds were redox-inactive. Thus, in contrast to other thiosemicarbazones with potent antiproliferative activity, Fe chelation and mobilization rather than free radical generation played a significant role in the cytotoxic effects of the current ligands.
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Chem. Res. Toxicol. · Jul 2008
Quantitation of pyridylhydroxybutyl-DNA adducts in liver and lung of F-344 rats treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and enantiomers of its metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol.
The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent pulmonary carcinogen in rats and is believed to be one cause of lung cancer in smokers. NNK is metabolized to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), which is also a strong lung carcinogen in rats and has a chiral center at its 1-carbon. Previous studies have demonstrated that cytochrome P450-catalyzed alpha-hydroxylation of NNK in the lung leading to the formation of methyl and pyridyloxobutyl (POB)-DNA adducts is critical for its carcinogenicity. alpha-Hydroxylation of NNAL would similarly produce pyridylhydroxybutyl (PHB)-DNA adducts, but these have not been previously investigated in vivo. ⋯ In the rats treated with NNK or (S)-NNAL, levels of each adduct at each time point were remarkably similar in lung, and levels of O(2)-PHB-dThd were generally greater than 7-PHB-Gua > O(6)-PHB-dGuo. The highest PHB-DNA adduct levels were found in lung and liver of rats treated with (R)-NNAL, suggesting that there are cytochrome P450s that efficiently catalyze the alpha-methyl hydroxylation of this compound. The results of this study provide further support for our hypothesis that (S)-NNAL is rapidly formed from NNK, sequestered at an unknown site in the lung, and then released and reoxidized to NNK with consequent DNA adduct formation resulting in lung carcinogenicity.
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Chem. Res. Toxicol. · Dec 2007
Time-dependent formation of 8-oxo-deoxyguanosine in the lungs of mice exposed to cigarette smoke.
Active and passive smoking are major risk factors for lung cancer. Pro-oxidants in tobacco smoke have been implicated in smoking-associated disease development due to their potential role in inducing oxidative stress. Previous studies have failed to associate increased levels of oxidative damage to DNA with the formation of the potentially mutagenic lesion, 8-oxo-2-deoxyguanosine (8-oxodG), probably due to repair of this lesion. ⋯ The levels significantly declined 20 h after the cessation of smoke exposure (14.0+/-1.6/10(6) nucleotides), although they were still higher than the control. Our results strongly suggest that there is a significant increase in the 8-oxodG levels immediately after the cessation of smoking, which is repaired over time. This initial increase in 8-oxodG levels may lead to gene mutations, and accumulation of such mutations over time can eventually lead to malignant transformation of the cells.
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Chem. Res. Toxicol. · Mar 2007
ReviewPossible role of ammonia on the deposition, retention, and absorption of nicotine in humans while smoking.
This perspective presents an overview of the properties of tobacco smoke aerosol and the possible effect of ammonia on the deposition location, retention and the amount and rate of nicotine absorption during cigarette smoking. Three main mechanisms describe the absorption of smoke constituents: (A) gas-phase constituents deposit directly; (B) particles deposit and the constituents then diffuse through the particle into the biological buffer and then into the tissue; and (C) particulate phase constituents evaporate from the particles and then deposit from the gas phase. Nicotine from smoking deposits and is absorbed predominately in the lungs. ⋯ It is certain that no single measurement of tobacco or of smoke, especially one made under equilibrium conditions, can adequately characterize the time-dependent properties of mainstream smoke aerosol. Thus, the fraction of nonprotonated freebase nicotine in trapped, aged smoke particulate matter has not been shown to be a useful predictor of the amount or total rate of nicotine uptake in human smokers. Similarly, "smoke pH" and "pHeff" are not useful practical parameters for providing understanding or predictability of tobacco smoke chemistry or nicotine bioavailability.
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Chem. Res. Toxicol. · Aug 2004
On the deposition of volatiles and semivolatiles from cigarette smoke aerosols: relative rates of transfer of nicotine and ammonia from particles to the gas phase.
The hypothesis that elevated levels of ammonia-releasing compounds in tobacco and ammonia in mainstream (MS) smoke increase the rate and amount of nicotine evaporation from the particles of MS smoke aerosol was examined by kinetic modeling and experiments with MS cigarette smoke. Computational simulation of a kinetic mechanism describing volatile loss of nicotine, ammonia, and acetic acid from an aqueous solution was used to compute the time-dependent concentration of all species in the model. Because of the high volatility of ammonia relative to that of nicotine, variation over a wide range of initial ammonia concentration had no significant effect upon the rate of loss of nicotine from the model system. ⋯ Included in these experiments are cigarettes that differ in their MS smoke ammonia content by a factor of ca. five. However, an increased amount of MS smoke ammonia does not increase the rate of nicotine loss from the particles. The combined results support the conclusion that ammonia in mainstream smoke has little effect, if any, upon the rate and amount of nicotine evaporation from MS smoke particles.