Tobacco-specific N-nitrosamines (TSNAs), including N'-nitrosonornicotine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, N'-nitrosoanatabine, and N'-nitrosoanabasine, have been implicated as a source of carcinogenicity in tobacco and cigarette smoke. We present a rapid and effective method comprising SPE based on tetraazacalix[2]arene[2]triazine-modified silica as sorbent and analysis with HPLC-MS/MS for the determination of TSNAs and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a metabolite of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, in rabbit plasma. The linear dynamic ranges were 10-2000 pg/mL for NNAL and 4-2000 pg/mL for the four TSNAs with good correlation coefficients (>0.9965). The LODs were in the range of 0.9-3.7 pg/mL, and the LOQs were between 2.9 and 12.3 pg/mL. The accuracies of the method were also evaluated and found to be in the range of 90.1-113.3%. This method is promising to be applied to the preconcentration and determination of TSNAs and NNAL in smoke and human body fluids.
A hydrophilic interaction liquid chromatographic-tandem mass spectrometric (HILIC-MS-MS) method for investigation of the in vivo metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a potent carcinogen, in rabbit blood has been developed and validated. This method achieved excellent repeatability and accuracy. Recovery ranged from 76.9 to 116.3 % and precision (as RSD) between 0.53 and 6.52 %. Linearity was good for all compounds (R(2)>0.9990) and the limit of detection (LOD) ranged from 0.016 to 0.082 ng mL(-1). Pharmacokinetic analysis indicated that NNK was rapidly eliminated in vivo in rabbit blood and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) was the major metabolite. The hydroxy acid, keto acid, and NNAL-N-oxide were also important metabolites in rabbit blood. It is probable that α-methylene hydroxylation was the major pathway of α-hydroxylation of NNK and NNAL in the rabbit.
A hydrophilic-interaction liquid chromatography-tandem mass spectrometry (HILIC-MS-MS) method was developed for the determination of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its metabolites in mouse liver and lung. The limits of detection of all analytes were in the range 0.017-0.057 ng mL(-1), and recovery ranged from 88.4-119.8 % with intra and inter-day precision in the range 0.89-6.03 % and 1.01-6.97 %, respectively. This simple and accurate method was used to evaluate the effect of chronic alcohol consumption on NNK bioactivation in mouse tissue. Time-course curves for NNK and its metabolites were generated, and the areas under the curves (AUCs) were compared. It was found that target tissues of NNK carcinogenesis in C57BL/6 mice contained high levels of α-hydroxylation metabolites of NNK and its carbonyl reduction metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). The most pronounced effect of alcohol was to enhance α-hydroxylation of NNK in mouse lung and liver, which suggests that chronic alcohol consumption may increase the risk of carcinogenicity associated with NNK in mice.
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