Chemical Studies on Tobacco Smoke: LI: Studies on Non-Volatile Nitrosamines in Tobacco

Hecht, Stephen S.; Chen, Chi hong B.; Dong, Michael W.; Hoffmann, Dietrich; Tso, T. C.

doi:10.2478/cttr-2013-0419

Cited by 31 publications

(31 citation statements)

References 11 publications

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“…B(a)P (purity >97%) and cottonseed oil were obtained from Sigma Chemical Co., (St. Louis, MO). NNK was synthesized by a published method (50). Other reagents used were obtained from commercial sources at the highest purity available.…”

Section: Methodsmentioning

confidence: 99%

Phenethyl Isothiocyanate and Sulforaphane and their N-Acetylcysteine Conjugates Inhibit Malignant Progression of Lung Adenomas Induced by Tobacco Carcinogens in A/J Mice

et al. 2005

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We have shown previously that naturally occurring isothiocyanates derived from cruciferous vegetables and their N-acetylcysteine conjugates inhibit lung adenoma formation induced by tobacco carcinogens in A/J mice at the postinitiation stage. The tumor-inhibitory activity by these compounds is linked with activation of activator protein and induction of apoptosis in lung tissues, suggesting that these compounds may also inhibit the development of adenomas to adenocarcinomas in lung. In this study, the chemopreventive activity of phenethyl isothiocyanate and sulforaphane and their N-acetylcysteine conjugates during progression of lung adenomas to malignant tumors was investigated in A/J mice. Mice were divided into 14 groups and treated with a mixture of 3 Mmol benzo(a)pyrene [B(a)P] and 3 Mmol 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) given by gavage once weekly for 8 weeks. Twenty weeks after the beginning of carcinogen administration, a total of 20 mice in the treatment groups were sacrificed with an average yield of 7.3 F 4.5 lung adenomas per mouse. The remaining mice in each group were fed diets containing phenethyl isothiocyanate (3 and 1.5 mmol/kg diet), sulforaphane (3 and 1.5 mmol/kg diet), phenethyl isothiocyanate-N-acetylcysteine (8 and 4 mmol/kg diet), sulforaphane-N-acetylcysteine (8 and 4 mmol/kg diet) during weeks 21 to 42. Four mice in each of the high-dose treatment groups were sacrificed during weeks 28 and 36 and the bioassay was terminated during week 42; lung tissues were harvested for histopathologic examination of tumors and for cell proliferation (proliferating cell nuclear antigen) and apoptosis (caspase-3) assays using immunohistochemical staining. At termination, the incidence of adenocarcinoma in the 3 mmol/kg diet phenethyl isothiocyanate group and 8 mmol/kg diet phenethyl isothiocyanate-N-acetylcysteine group was reduced to 19% and 13%, respectively, compared with 42% in the carcinogen-treated control group. At the lower doses, phenethyl isothiocyanate and its N-acetylcysteine conjugate also inhibited the incidences of lung adenocarcinoma, however, the decreases were not statistically significant. The lung tumor incidences in groups treated with sulforaphane-N-acetylcysteine in the diet were also significantly reduced to 11% or 16%. Furthermore, the malignant lung tumor multiplicity was significantly reduced from 1.0 tumor/ mouse in the carcinogen-treated control group to 0.3 in the sulforaphane low-dose group, 0.3 and 0.4 in the two sulforaphane-N-acetylcysteine groups, and 0.4 in the phenethyl isothiocyanate high-dose group. The malignant tumor multiplicities in other treatment groups were also reduced (0.5-0.8 tumors/mouse), but not significantly. Unlike lung adenocarcinomas, both incidences and multiplicities of lung adenomas were not much affected by treatment with isothiocyanates or their conjugates. Immunohistochemical examination of the lung tumors from all time points indicated that significant reduction in proliferating cell nuclear antigen and induction...

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Section: Methodsmentioning

confidence: 99%

Phenethyl Isothiocyanate and Sulforaphane and their N-Acetylcysteine Conjugates Inhibit Malignant Progression of Lung Adenomas Induced by Tobacco Carcinogens in A/J Mice

et al. 2005

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“…Myosmine (HPLC purity Ͼ99%) and keto acid (HPLC purity Ͼ98%) were synthesized according to the method of Brandänge and Lindblom (1976) and McKennis et al (1964b), respectively. Synthesis of HPB (HPLC purity Ͼ99%) and 3Ј-hydroxymyosmine (HPLC purity Ͼ97%) was performed in accordance with the method of Hecht et al (1977) and Hecht et al (1980a), respectively. The physicochemical parameters of the products were in accordance with values reported in the literature.…”

Section: Methodsmentioning

confidence: 99%

Metabolism of Myosmine in Wistar Rats

Zwickenpflug

Tyroller²,

Richter³

2005

Drug Metab Dispos

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ABSTRACT:The alkaloid myosmine is present not only in tobacco products but also in various foods. Myosmine is easily nitrosated, yielding 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB) and the esophageal tobacco carcinogen N-nitrosonornicotine. Due to its widespread occurrence, investigations on the metabolism and activation of myosmine are needed for risk assessment. Therefore, the metabolism of myosmine has been studied in Wistar rats treated with single oral doses of [pyridine-5-3 H]myosmine at 0.001, 0.005, 0.5, and 50 mol/kg body weight. Oral administration was achieved by feeding a labeled apple bite. Radioactivity was completely recovered in urine and feces within 48 h. At the two lower doses, 0.001 and 0.005 mol/kg, a higher percentage of the radioactivity was excreted in urine (86.2 ؎ 4.9% and 88.9 ؎ 1.7%) as compared with the higher doses, 0.5 and 50 mol/kg, where only 77.8 ؎ 7.3% and 75.4 ؎ 6.6% of the dose was found in urine. Within 24 h, urinary excretion of radioactivity was nearly complete with less than 4% of the total urinary output appearing between 24 and 48 h. The two major metabolites accounting for >70% of total radioactivity in urine were identified as 3-pyridylacetic acid (20-26%) and 4-oxo-4-(3-pyridyl)butyric acid (keto acid, 50-63%) using UV-diode array detection and gas chromatography-mass spectrometry measurements. 3-Pyridylmethanol (3-5%), 3-hydroxymyosmine (2%) and HPB (1-3%) were detected as minor metabolites. 3-Hydroxymyosmine is exclusively formed from myosmine and therefore might be used as a urinary biomarker for myosmine exposure in the future.

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“…Synthesis of NNK has been described, and its purity was greater than 99% by high performance liquid chromatography (HPLC) (7). Sodium borohydride reduction of NNK gave 4-(methylnitrosamino)-1-(3-pyridyl)-butan-1-ol (NNAl) which was free of any traces of NNK by reverse phase HPLC.…”

Section: Chemicalsmentioning

confidence: 99%

“…As with most N-nitrosamines, hydroxylation of the carbon a to the N-nitroso group of NNK and NNAI could be considered a crucial and rate-limiting step in their bioactivation to alkylating species. For instance, a-methylene hydroxylation of NNK and NNAI would lead to the generation of methyldiazohydroxide (7). The keto acid and hydroxy acid (compounds 10 and 11 of Fig.…”

Section: Chemicalsmentioning

confidence: 99%

Study of DNA methylation by tobacco-specific N-nitrosamines.

Castonguay¹,

Foiles²,

Trushin³

et al. 1985

Environ Health Perspect

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An enzyme-linked immunosorbent assay (BA-ELISA) involving use of biotin-labeled anti-rabbit IgG and avidin-labeled horseradish peroxidase was developed for the measurement of 06-methyl-2'-deoxyguanosine (06-MedGuo). Up to 5 jg of methylated DNA was enzymatically hydrolyzed, and the extent of inhibition of binding of immobilized 06-MedGuo-bovine serum albumin to rabbit anti-O6-MedGuo was measured. Fifty percent inhibition of antigen-antibody binding was achieved with 2.5 pmole of of 06-MedGuo. Separation of 0-MedGuo from unmodified nucleosides by high-performance liquid chromatography (HPLC-BA-ELISA) allowed detection of 700 fmole 06-MedGuo in 1 mg of DNA.Among the tobacco-related carcinogens, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one of the most potent. In F344 rats it induces nasal cavity, lung and liver tumors. Four hours after a single IV injection of NNK to F344 rats (87 mg/kg body weight), 0'-MedGuo was present in target organs (,umole 0'-MedGuo/mole dGuo) (nasal mucosa, 219; lung, 13.2; and liver, 34.5) but was not detectable in nontarget organs. F344 rats receiving daily IP injections of NNK (40 mg/kg body weight) for 14 days were sacrificed 24 hr after the last injection. The levels of (06-Medguo/dGuo) were 7.9 and 11.4 ,umole/mole in the nasal mucosa and lung, respectively. In the liver no 06-MedGuo was detected, but 1050 ,umole of 7-MeGua/mole Gua was measured by HPLC-fluorimetry. No DNA methylation was observed in the nasal mucosa or liver of F344 rats treated with the nicotine-derived carcinogen N'-nitrosonornicotine. Reduction of the carbonyl of NNK is a major metabolic pathway, giving rise to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butan-1-ol (NNAI). Nasal mucosae were cultured in vitro with NNK or NNAI. After 1 hr, methylation at the 06-dGuo and 7-dGuo sites were observed with NNK but not with NNAI. Methylation by NNAI after 24 hr was associated with the conversion of NNAI to NNK. These results suggest that NNAI is not associated with the activation of NNK to DNA methylating species.

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Chemical Studies on Tobacco Smoke: LI: Studies on Non-Volatile Nitrosamines in Tobacco

Cited by 31 publications

References 11 publications

Phenethyl Isothiocyanate and Sulforaphane and their N-Acetylcysteine Conjugates Inhibit Malignant Progression of Lung Adenomas Induced by Tobacco Carcinogens in A/J Mice

Phenethyl Isothiocyanate and Sulforaphane and their N-Acetylcysteine Conjugates Inhibit Malignant Progression of Lung Adenomas Induced by Tobacco Carcinogens in A/J Mice

Metabolism of Myosmine in Wistar Rats

Study of DNA methylation by tobacco-specific N-nitrosamines.

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