Effect of nicotine and tobacco-specific nitrosamines on the metabolism of <i>N'</i>-nitrosonornicotine and 4-(methylnitrosamino)-1-(3pyridyl)-1-butanone by rat oral tissue

Murphy, Sharon E.; Heiblum, R.

doi:10.1093/carcin/11.9.1663

Cited by 41 publications

(51 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Exposure to nicotine caused a statistically significant increase in micronucleus frequency in human gingival fibroblasts in vitro [25]. However, it has been demonstrated that nicotine inhibits the action of nitrosamines which is catalyzed by P450 2E1 [26,27], and also it participates in the conversion of benzo[a]pyrene to DNA-reactive metabolites [28]. Nitrosamines and polycyclic aromatic amines are considered important chemical agents able to promote genetic insult as far as carcinogenesis [15].…”

Section: Discussionmentioning

confidence: 99%

Cytogenetic Biomonitoring in Buccal Mucosa Cells from Young Smokers

et al. 2015

View full text Add to dashboard Cite

Objective: Nowadays, much attention has been focused on the search for new non-invasive methodologies able to predict malignant transformation of oral mucosa cells. The aim of the present study was to comparatively evaluate DNA damage (micronucleus) and cellular death (pyknosis, karyolysis and karyorrhexis) in exfoliated oral mucosa cells from smokers and non-smokers in buccal mucosa cells. Study Design: A total of 24 young, healthy smokers and 14 non-smokers were included in this setting. Individuals had epithelial cells from the cheek mechanically exfoliated, placed in fixative and dropped in clean slides which were checked for the above nuclear phenotypes. Results: Smokers presented more (p < 0.05) micronucleated oral mucosa cells than non-smokers. Tobacco smoke was not able to increase other nuclear alterations closely related to cytotoxicity such as karyorrhexis, pyknosis and karyolysis. Conclusion: In summary, these data indicate that the cigarette is able to induce micronuclei in oral mucosa cells, so the micronucleus test is a suitable method for predicting oral cancer risk.

show abstract

Section: Discussionmentioning

confidence: 99%

Cytogenetic Biomonitoring in Buccal Mucosa Cells from Young Smokers

et al. 2015

View full text Add to dashboard Cite

show abstract

“…A number of in vitro studies have shown that 2′-hydroxylation of NNN is favored in rat esophagus compared to 5′-hydroxylation (13)(14)(16)(17), and POB-DNA adducts derived from NNN 2′-hydroxylation have been detected in rat esophagus cultured with [5-3 H]NNN, as measured by HPB released by acid hydrolysis (10). The results of the current study are consistent with these findings and demonstrate for the first time the in vivo formation of POB-DNA adducts in the esophagus of NNN-treated rats.…”

Section: Discussionmentioning

confidence: 99%

“…Structures of POB-DNA adducts (10)(11)(12)(13)(14)(15) and DNA adducts derived from 5′-hydroxylation of NNN (16 and 17). dR: 2′-deoxyribosyl.…”

Section: Abbreviationsmentioning

confidence: 99%

“…5′-Hydroxylation of NNN leads to intermediate 9 which is also DNA reactive, yielding adducts 16 and 17 (Chart 2) (12). 2′-Hydroxylation is believed to be the major bioactivation pathway of NNN in rats based on previous studies in which it was the predominant metabolic pathway in both rat esophagus and nasal cavity, target tissues for NNN tumorigenicity, and POB-DNA adducts were detected in these tissues as HPB-releasing DNA adducts (9)(10)(11)(13)(14)(15)(16)(17) However, individual POB-DNA adducts of NNN have not been previously analyzed in vitro or in vivo.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Analysis of Pyridyloxobutyl DNA Adducts in F344 Rats Chronically Treated with (R)- and (S)-N‘-Nitrosonornicotine

Lao

Kassie

et al. 2007

Chem. Res. Toxicol.

View full text Add to dashboard Cite

NNN (1) is an esophageal carcinogen in rats. 2'-Hydroxylation of NNN is believed to be the major bioactivation pathway for NNN tumorigenicity. (S)-NNN is preferentially metabolized by 2'-hydroxylation in cultured rat esophagus, whereas there is no preference for 2'-hydroxylation versus 5'-hydroxylation in the metabolism of (R)-NNN. 2'-Hydroxylation of NNN generates the reactive intermediate 4-oxo-4-(3-pyridyl)butanediazohydroxide (8), resulting in the formation of pyridyloxobutyl (POB)-DNA adducts. On the basis of these observations, we hypothesized that (S)-NNN treatment would produce higher levels of POB-DNA adducts than that by (R)-NNN in the rat esophagus. We tested this hypothesis by treating male F344 rats with 10 ppm of (R)-NNN or (S)-NNN in drinking water. After 1, 2, 5, 10, 16, or 20 weeks of treatment, POB-DNA adducts in esophageal, liver, and lung DNA were quantified by HPLC-ESI-MS/MS. In the rat esophagus, (S)-NNN treatment generated levels of POB-DNA adducts 3-5 times higher than (R)-NNN treatment, which supports our hypothesis. 7-[4-(3-Pyridyl)-4-oxobut-1-yl]guanine (7-POB-Gua, 14) was the major adduct detected, followed by O2-[4-(3-pyridyl)-4-oxobut-1-yl]thymidine (O2-POB-dThd, 11) and O2-[4-(3-pyridyl)-4-oxobut-1-yl]cytosine (POB-Cyt, 15). O6-[4-(3-Pyridyl)-4-oxobut-1-yl]-2'-deoxyguanosine (O6-POB-dGuo, 10) was not detected. The total POB-DNA adduct levels in the esophagus were 3-11 times higher than those in the liver for (R)-NNN and 2-6 times higher than those for (S)-NNN. In contrast to the esophagus and liver, (R)-NNN treatment produced more POB-DNA adducts than (S)-NNN treatment in the rat lung, which suggested an important role for cytochrome P450 2A3 in NNN metabolism in the rat lung. In both the liver and lung, O2-POB-dThd was the predominant adduct and accumulated during the experiment. The results of this study demonstrate that individual POB-DNA adducts form and persist in the esophagi, livers, and lungs of rats chronically treated with NNN enantiomers and demonstrate that (S)-NNN produces higher levels of POB-DNA adducts in the esophagus than (R)-NNN, suggesting that (S)-NNN is more tumorigenic than (R)-NNN to the rat esophagus.

show abstract

“…Therefore, experiments were performed to investigate wether nicotine and its main metabolite cotinine affect NNK metabolism in intact organs. In several studies nicotine has been shown to inhibit the metabolic activation of NNK in vivo (Richter and Tricker 1994;Kutzer et al 1995) and in vitro (Murphy and Heiblum 1990;Hong et al 1992).…”

Section: Discussionmentioning

confidence: 99%

Effect of nicotine or cotinine on metabolism of 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) in isolated rat lung and liver

Schulze

Schrader

Foth

et al. 1998

Naunyn-Schmiedeberg's Arch Pharmacol

View full text Add to dashboard Cite

The scope of the present study was to investigate whether nicotine or cotinine will affect the metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in isolated perfused rat lungs and livers and to study the effect of starvation on pulmonary metabolism of NNK. NNK metabolism was investigated in isolated perfused liver and lung of male F344 rats perfused with 35 nM [5-3H]NNK in presence of a 1400-fold excess of the main tobacco alkaloid nicotine and its metabolite cotinine. In perfused rat livers, nicotine and cotinine inhibited NNK elimination and metabolism and led to a substantial increase of elimination half-life from 14.6 min in controls to 25.5 min after nicotine and 36.6 min after cotinine co-administration, respectively. In parallel, the pattern of NNK metabolites was changed by nicotine and cotinine. The pathway of alpha-hydroxylation representing the metabolic activation of NNK was decreased to 77% and 85% of control values, whereas N-oxidation of NNK and glucuronidation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) was increased 2.6- and 1.2-fold in presence of nicotine and cotinine, respectively. When isolated rat lungs were perfused with 35 nM NNK for 3 h neither the elimination nor the pattern of metabolites were substantially affected due to co-administration of 50 microM nicotine or cotinine. Cytochrome P450 2E1 is known to participate in the activation of NNK and can be induced by starvation. However, isolated rat lungs from male Sprague Dawley rats perfused with [1-14C]NNK at about 2 microM for 3 h, revealed only small differences in pulmonary elimination and pattern of NNK metabolites between fed and starved animals. These results suggest that nicotine and its main metabolite cotinine inhibit the metabolic activation of NNK predominantly in the liver whereas activation in lung, a main target organ of NNK induced carcinogenesis, remained almost unaffected.

show abstract

Effect of nicotine and tobacco-specific nitrosamines on the metabolism of N'-nitrosonornicotine and 4-(methylnitrosamino)-1-(3pyridyl)-1-butanone by rat oral tissue

Cited by 41 publications

References 0 publications

Cytogenetic Biomonitoring in Buccal Mucosa Cells from Young Smokers

Cytogenetic Biomonitoring in Buccal Mucosa Cells from Young Smokers

Analysis of Pyridyloxobutyl DNA Adducts in F344 Rats Chronically Treated with (R)- and (S)-N‘-Nitrosonornicotine

Effect of nicotine or cotinine on metabolism of 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) in isolated rat lung and liver

Contact Info

Product

Resources

About