Chemical research in toxicology
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Chem. Res. Toxicol. · Feb 2003
Molecular characterization of mitomycin C-induced large deletions and tandem-base substitutions in the bone marrow of gpt delta transgenic mice.
Deletion mutations constitute an important class of mutations that may result in a variety of human diseases, including cancer. Although many chemicals and ionizing radiations induce deletions, this class of mutation has been poorly characterized at the molecular level, particularly in vivo. Here we report the molecular nature of deletions as well as base substitutions induced by antitumor antibiotic mitomycin C (MMC) in the bone marrow using a novel transgenic mouse, gpt delta. ⋯ Previous in vitro studies report the induction of single-base substitutions and single-base deletions by MMC. However, no such mutations were identified in vivo. Thus, our results strongly caution that in vitro mutation spectra do not necessarily reflect genotoxic events in vivo and emphasize the importance of transgenic rodent genotoxicity assays to examine the roles of DNA adducts in mutagenesis and carcinogenesis.
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Chem. Res. Toxicol. · Jan 2003
Fraction of free-base nicotine in fresh smoke particulate matter from the Eclipse "cigarette" by 1H NMR spectroscopy.
Solution 1H NMR (proton-NMR) spectroscopy was used to measure the distribution of nicotine between its free-base and protonated forms at 20 degrees C in (a) water; (b) glycerin/water mixtures; and (c) puff-averaged "smoke" particulate matter (PM) produced by the Eclipse cigarette, a so-called "harm reduction" cigarette manufactured by R. J. Reynolds (RJR) Tobacco Co. ⋯ The effective pH of the Eclipse smoke PM at 20 degrees C may then be calculated as pHeff = 8.06 + log[alpha fb/(1-alpha fb)] = 6.69, where 8.06 is the pKa of NicH+ in water at 20 degrees C. The measurements obtained for the puff-averaged Eclipse smoke PM pertain to the chemistry of the smoke PM as it might be initially inhaled at 20 degrees C. Upon inhalation, the volatilization of nicotine and other acid/base active compounds (as well as a warming toward a body temperature of 37 degrees C) will alter the pHeff value of the smoke PM during the time that it resides and ages in the respiratory tract.
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Chem. Res. Toxicol. · Jan 2003
The pyridyloxobutyl DNA adduct, O6-[4-oxo-4-(3-pyridyl)butyl]guanine, is detected in tissues from 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-treated A/J mice.
The tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is a potent pulmonary carcinogen. This unsymmetric nitrosamine can be metabolically activated to lung DNA methylating and pyridyloxobutylating intermediates. The methyl DNA adducts are well characterized. ⋯ O6-mG and O6-pobG were removed from DNA to the same extent in a competitive assay, suggesting that low levels of O6-pobG in lungs of NNK-treated mice did not result from preferential repair of O6-pobG by AGT. It is more likely that initial levels of O6-pobG are much lower than initial levels of O6-mG in lung DNA from NNK-treated A/J mice. These data are consistent with previous studies, which indicate that DNA methylation is the critical pathway for NNK-induced lung carcinogenesis in A/J mice.
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Chem. Res. Toxicol. · Apr 2002
Analysis of N- and O-glucuronides of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in human urine.
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a tobacco-specific lung carcinogen which may play an important role as a cause of lung cancer in smokers. NNK is extensively metabolized to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), which like NNK is a potent pulmonary carcinogen. NNAL in turn is glucuronidated, and both NNAL and its glucuronides are excreted in human urine. ⋯ This difference was significant (P = 0.01), suggesting that smoking induces glucuronidation of NNAL. The results of this study demonstrate that NNAL-N-Gluc contributes substantially to NNAL-glucuronides in human urine. These results are important for a clearer understanding of mechanisms of detoxification of NNK in humans.
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Chem. Res. Toxicol. · Nov 2001
ReviewA consideration of the role of gas/particle partitioning in the deposition of nicotine and other tobacco smoke compounds in the respiratory tract.
Tobacco smoke is an aerosol that contains both gaseous and suspended particulate material (PM). The particles are largely liquid droplets containing a wide variety of condensed organic compounds. Each compound in the smoke will partition between the gas and PM phases and will always seek a state of gas/particle equilibrium. ⋯ This conclusion is consistent with (1) the gas-sampling denuder results obtained by Philip Morris in which significant tobacco smoke nicotine was observed to deposit in acid-coated denuder tubes, with more depositing when the cigarette tobacco blend was treated with ammonia; (2) the view that the sensory "impact" exhibited by some tobacco smokes is caused by the deposition of gaseous nicotine in the pharynx; (3) the observed throat irritation caused by nicotine inhalers; and (4) the high overall respiratory tract deposition efficiencies for nicotine of 0.9 and greater that have been reported for some cigarette smokes. The available information combines to create a picture of nicotine in cigarette smoke that contradicts the traditional view that cigarette smoke PM is typically acidic, with little free-base nicotine typically present in the smoke PM phase. Government agencies interested in establishing a framework for the testing and monitoring of nicotine delivery may wish to consider requiring the measurement and publication of the PM-phase alpha(fb) values for the cigars and cigarettes marketed in their jurisdictions.