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Agonist and antagonist effects of tobacco-related nitrosamines on human α4β2 nicotinic acetylcholine receptors.

Brusco S, Ambrosi P, Meneghini S, Becchetti A - Front Pharmacol (2015)

Bottom Line: However, the functional effects of these drugs on specific nAChR subtypes are largely unknown.The effects of both NNK and NNN were mainly competitive and largely independent of Vm.The different actions of NNN and NNK must be taken into account when interpreting their biological effects in vitro and in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca Milano, Italy.

ABSTRACT
Regulation of the "neuronal" nicotinic acetylcholine receptors (nAChRs) is implicated in both tobacco addiction and smoking-dependent tumor promotion. Some of these effects are caused by the tobacco-derived N-nitrosamines, which are carcinogenic compounds that avidly bind to nAChRs. However, the functional effects of these drugs on specific nAChR subtypes are largely unknown. By using patch-clamp methods, we tested 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) on human α4β2 nAChRs. These latter are widely distributed in the mammalian brain and are also frequently expressed outside the nervous system. NNK behaved as a partial agonist, with an apparent EC50 of 16.7 μM. At 100 μM, it activated 16% of the maximal current activated by nicotine. When NNK was co-applied with nicotine, it potentiated the currents elicited by nicotine concentrations ≤ 100 nM. At higher concentrations of nicotine, NNK always inhibited the α4β2 nAChR. In contrast, NNN was a pure inhibitor of this nAChR subtype, with IC50 of approximately 1 nM in the presence of 10 μM nicotine. The effects of both NNK and NNN were mainly competitive and largely independent of Vm. The different actions of NNN and NNK must be taken into account when interpreting their biological effects in vitro and in vivo.

No MeSH data available.


Related in: MedlinePlus

Molecular structures of nicotine, NNK, and NNN. NNN and NNK are the two most potent carcinogenic N-nitrosamines. They derive from nitrosation of nicotine, which occurs during tobacco treatment and storage as well as through metabolic processing in mammals.
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Figure 1: Molecular structures of nicotine, NNK, and NNN. NNN and NNK are the two most potent carcinogenic N-nitrosamines. They derive from nitrosation of nicotine, which occurs during tobacco treatment and storage as well as through metabolic processing in mammals.

Mentions: The complex pattern of nAChR expression may partly explain the pleiotropic effects of smoking. In the brain, uncontrolled stimulation of nAChRs is thought to mediate the addictive effects of tobacco (Changeux, 2010). In other tissues, smoking can produce toxic as well as carcinogenic effects. These latter depend on long-term exposure to several tobacco metabolites, especially the N-nitrosamines (here simply referred to as “nitrosamines”; Hecht and Hoffmann, 1988). When metabolically activated, these drugs cause DNA mutations, particularly G to T transversions that may lead to mutation of k-ras and p53 (Pfeifer et al., 2002). Nonetheless, many harmful effects of the tobacco-related nitrosamines may be attributed to direct targeting of nAChRs. In fact, the nitrosamines that produce the most potent biological effects are structural analogs of either ACh (e.g., diethylnitrosamine) or nicotine (especially NNK and NNN; Figure 1). All of these compounds can bind to nAChRs (Schuller and Orloff, 1998; Schuller, 2007). Although nicotine is not carcinogenic, engagement of nAChRs with either nicotine or nitrosamines can promote the neoplastic progression in cultured cells, by stimulating cell cycle, migration, angiogenesis, epithelial-to-mesenchymal transition, and inhibiting apoptosis (Schuller, 1989; Maneckjee and Minna, 1990; Heeschen et al., 2001; Arredondo et al., 2006; Guo et al., 2008; Paleari et al., 2008; Song et al., 2008; Al-Wadei and Schuller, 2009; Calleja-Macias et al., 2009; Dasgupta et al., 2009). Similar evidence is slowly accumulating in vivo (Heeschen et al., 2001; Paleari et al., 2009).


Agonist and antagonist effects of tobacco-related nitrosamines on human α4β2 nicotinic acetylcholine receptors.

Brusco S, Ambrosi P, Meneghini S, Becchetti A - Front Pharmacol (2015)

Molecular structures of nicotine, NNK, and NNN. NNN and NNK are the two most potent carcinogenic N-nitrosamines. They derive from nitrosation of nicotine, which occurs during tobacco treatment and storage as well as through metabolic processing in mammals.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4585029&req=5

Figure 1: Molecular structures of nicotine, NNK, and NNN. NNN and NNK are the two most potent carcinogenic N-nitrosamines. They derive from nitrosation of nicotine, which occurs during tobacco treatment and storage as well as through metabolic processing in mammals.
Mentions: The complex pattern of nAChR expression may partly explain the pleiotropic effects of smoking. In the brain, uncontrolled stimulation of nAChRs is thought to mediate the addictive effects of tobacco (Changeux, 2010). In other tissues, smoking can produce toxic as well as carcinogenic effects. These latter depend on long-term exposure to several tobacco metabolites, especially the N-nitrosamines (here simply referred to as “nitrosamines”; Hecht and Hoffmann, 1988). When metabolically activated, these drugs cause DNA mutations, particularly G to T transversions that may lead to mutation of k-ras and p53 (Pfeifer et al., 2002). Nonetheless, many harmful effects of the tobacco-related nitrosamines may be attributed to direct targeting of nAChRs. In fact, the nitrosamines that produce the most potent biological effects are structural analogs of either ACh (e.g., diethylnitrosamine) or nicotine (especially NNK and NNN; Figure 1). All of these compounds can bind to nAChRs (Schuller and Orloff, 1998; Schuller, 2007). Although nicotine is not carcinogenic, engagement of nAChRs with either nicotine or nitrosamines can promote the neoplastic progression in cultured cells, by stimulating cell cycle, migration, angiogenesis, epithelial-to-mesenchymal transition, and inhibiting apoptosis (Schuller, 1989; Maneckjee and Minna, 1990; Heeschen et al., 2001; Arredondo et al., 2006; Guo et al., 2008; Paleari et al., 2008; Song et al., 2008; Al-Wadei and Schuller, 2009; Calleja-Macias et al., 2009; Dasgupta et al., 2009). Similar evidence is slowly accumulating in vivo (Heeschen et al., 2001; Paleari et al., 2009).

Bottom Line: However, the functional effects of these drugs on specific nAChR subtypes are largely unknown.The effects of both NNK and NNN were mainly competitive and largely independent of Vm.The different actions of NNN and NNK must be taken into account when interpreting their biological effects in vitro and in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca Milano, Italy.

ABSTRACT
Regulation of the "neuronal" nicotinic acetylcholine receptors (nAChRs) is implicated in both tobacco addiction and smoking-dependent tumor promotion. Some of these effects are caused by the tobacco-derived N-nitrosamines, which are carcinogenic compounds that avidly bind to nAChRs. However, the functional effects of these drugs on specific nAChR subtypes are largely unknown. By using patch-clamp methods, we tested 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) on human α4β2 nAChRs. These latter are widely distributed in the mammalian brain and are also frequently expressed outside the nervous system. NNK behaved as a partial agonist, with an apparent EC50 of 16.7 μM. At 100 μM, it activated 16% of the maximal current activated by nicotine. When NNK was co-applied with nicotine, it potentiated the currents elicited by nicotine concentrations ≤ 100 nM. At higher concentrations of nicotine, NNK always inhibited the α4β2 nAChR. In contrast, NNN was a pure inhibitor of this nAChR subtype, with IC50 of approximately 1 nM in the presence of 10 μM nicotine. The effects of both NNK and NNN were mainly competitive and largely independent of Vm. The different actions of NNN and NNK must be taken into account when interpreting their biological effects in vitro and in vivo.

No MeSH data available.


Related in: MedlinePlus