The Experts below are selected from a list of 273 Experts worldwide ranked by ideXlab platform
Peter A Crooks - One of the best experts on this subject based on the ideXlab platform.
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The analgesic and toxic effects of Nornicotine enantiomers alone and in interaction with morphine in rodent models of acute and persistent pain
Pharmacology biochemistry and behavior, 2009Co-Authors: Joseph R. Holtman, Peter A Crooks, Jaime K. Johnson-hardy, Elzbieta P. WalaAbstract:Abstract Neuronal nicotinic acetylcholinic receptors (nAChR) are promising targets for the development of novel analgesics. Nicotine and other nAChR-agonists produce profound analgesia in rodent models of acute and persistent pain. However, significant side-effects are of concern. Nornicotine (N-desmethyl-nicotine) appears to activate different nAChR subtypes, has a better pharmacokinetic profile, and produces less toxicity than nicotine. Little is known about its analgesic properties. In the present study, the S(−)- and R(+)-enantiomers of Nornicotine were characterized with regard to analgesia and side-effects profile. Efficacy was demonstrated in rat models of pain where central sensitization is involved: i.e. the chronic constriction nerve injury model of peripheral neuropathy and the formalin model of tonic inflammatory pain. The desirable (analgesic) properties resided predominantly in the S(−)- rather than the R(+)-enantiomer. In contrast, undesirable effects (motor in-coordination, reduced locomotor activity, ataxia) were more pronounced with the R(+)-enantiomer. This is an interesting finding, which may suggest separation of toxicity from analgesia by utilization of S(−)-enantiomer of Nornicotine. Maximum analgesic effectiveness without significant side-effects was achieved when S(−)-Nornicotine (sub-analgesic dose) was combined with a low-dose of the µ-opioid, morphine. These preclinical data suggest that S(−)-Nornicotine may be of value, either alone or in combination with an opioid, for treatment of a broad-spectrum of pain (i.e. nociceptive, neuropathic, and mixed pain).
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The pharmacological activity of nicotine and Nornicotine on nAChRs subtypes: relevance to nicotine dependence and drug discovery
Journal of neurochemistry, 2007Co-Authors: Roger L. Papke, Linda P Dwoskin, Peter A CrooksAbstract:Cigarette smoking and other forms of tobacco use deliver an array of pharmacologically active alkaloids, including nicotine and ultimately various metabolites of these substances. While Nornicotine is a significant component in tobacco as well as a minor systemic metabolite of nicotine, Nornicotine appears to be N-demethylated locally in the brain where it accumulates at relatively high levels after chronic nicotine administration. We have now examined the effects of Nornicotine on specific combinations of neuronal nicotinic acetylcholine receptor (nAChR) subunits expressed in Xenopus oocytes and compared these responses to those evoked by acetylcholine and nicotine. Of the nAChR subtypes studied, we have found that alpha7 receptors are very responsive to Nornicotine (EC50 approximately 17 micromol/L I(max) 50%, compared with acetylcholine (ACh)). nAChRs containing the ligand-binding domain of the alpha6 subunits (in the form of an alpha6/alpha3 chimera) are also strongly responsive to Nornicotine (EC50 approximately 4 micromol/L I(max) 50%, compared with ACh). Alpha7-type nAChRs have been suggested to be potential therapeutic targets for Alzheimer's disease, schizophrenia and possibly other pathologies. nAChRs containing alpha6 subunits have been suggested to have a role in nicotine-evoked dopamine release. Thus, understanding the actions of Nornicotine in the brain may have significance for both emerging therapeutics and the management of nicotine dependence.
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Nornicotine inhibition of dopamine transporter function in striatum via nicotinic receptor activation.
Synapse (New York N.Y.), 2007Co-Authors: Lisa S. Middleton, Peter A Crooks, Peter J. Wedlund, Wayne A. Cass, Linda P DwoskinAbstract:Nornicotine, a tobacco alkaloid and N-demethylated nicotine metabolite, releases DA from superfused rat striatal slices in a mecamylamine-sensitive manner, indicating nicotinic receptor (nAChR) modulation of this response. The current study determined the effect of Nornicotine on rat striatal dopamine transporter (DAT) function using in vivo voltammetry. In a dose-related and mecamylamine-sensitive manner, Nornicotine (0.35-12.0 mg/kg, s.c.) decreased DA clearance, suggesting that Nornicotine inhibits striatal DAT function via a nAChR-mediated mechanism. Furthermore, the nAChRs mediating the Nornicotine-induced inhibition of DAT function appear to be different from those activated by nicotine which increases DA clearance. Understanding the actions of Nornicotine in brain may have significance for emerging therapeutics and for the management of nicotine dependence.
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Effects of Nornicotine enantiomers on intravenous S(−)-nicotine self-administration and cardiovascular function in rats
Psychopharmacology, 2006Co-Authors: D. J. Stairs, Peter A Crooks, Linda P Dwoskin, N. M. Neugebauer, X. Wei, C. Boustany, M. Hojahmat, L. A. Cassis, M. T. BardoAbstract:Previous neurochemical evidence indicates that R(+)-Nornicotine is more potent than S(-)-Nornicotine in evoking dopamine release in rat nucleus accumbens slices. The current study tested the hypothesis that R(+)-Nornicotine is also more potent than S(-)-Nornicotine in selectively decreasing intravenous S(-)-nicotine self-administration in rats. After acute pretreatment (1-10 mg/kg for each enantiomer), R(+)-Nornicotine was more potent than S(-)-Nornicotine in decreasing S(-)-nicotine self-administration; in contrast, within the same dose range, the Nornicotine enantiomers were equipotent in decreasing sucrose-maintained responding. This enantioselectivity does not likely reflect a difference in bioavailability, since similar levels of Nornicotine were recovered from the brain 60 min after injection (5.6 mg/kg for each enantiomer). With repeated pretreatment, tolerance did not develop to the rate-decreasing effect of either Nornicotine enantiomer (3 or 5.6 mg/kg) with respect to the decrease in S(-)-nicotine self-administration, although the enantioselectivity dissipated across repeated pretreatments. While both enantiomers acutely produced a similar increase in blood pressure and heart rate, tolerance developed to the blood pressure effects of R(+)-Nornicotine, but not to the effects of S(-)-Nornicotine, across repeated treatments. Both R(+)- and S(-)-Nornicotine may have potential utility as a novel tobacco use cessation agent.
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effects of Nornicotine enantiomers on intravenous s nicotine self administration and cardiovascular function in rats
Psychopharmacology, 2006Co-Authors: D. J. Stairs, Peter A Crooks, Linda P Dwoskin, N. M. Neugebauer, X. Wei, C. Boustany, M. Hojahmat, L. A. Cassis, M. T. BardoAbstract:Rationale Previous neurochemical evidence indicates that R(+)-Nornicotine is more potent than S(−)-Nornicotine in evoking dopamine release in rat nucleus accumbens slices.
Linda P Dwoskin - One of the best experts on this subject based on the ideXlab platform.
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Effects of Nornicotine enantiomers on intravenous S(−)-nicotine self-administration and cardiovascular function in rats
Psychopharmacology, 2007Co-Authors: D. J. Stairs, Linda P Dwoskin, N. M. Neugebauer, X. Wei, C. Boustany, M. Hojahmat, L. A. Cassis, P. A. Crooks, M. T. BardoAbstract:Rationale Previous neurochemical evidence indicates that R (+)-Nornicotine is more potent than S (−)-Nornicotine in evoking dopamine release in rat nucleus accumbens slices. Objective The current study tested the hypothesis that R (+)-Nornicotine is also more potent than S (−)-Nornicotine in selectively decreasing intravenous S (−)-nicotine self-administration in rats. Results After acute pretreatment (1–10 mg/kg for each enantiomer), R (+)-Nornicotine was more potent than S (−)-Nornicotine in decreasing S (−)-nicotine self-administration; in contrast, within the same dose range, the Nornicotine enantiomers were equipotent in decreasing sucrose-maintained responding. This enantioselectivity does not likely reflect a difference in bioavailability, since similar levels of Nornicotine were recovered from the brain 60 min after injection (5.6 mg/kg for each enantiomer). With repeated pretreatment, tolerance did not develop to the rate-decreasing effect of either Nornicotine enantiomer (3 or 5.6 mg/kg) with respect to the decrease in S (−)-nicotine self-administration, although the enantioselectivity dissipated across repeated pretreatments. While both enantiomers acutely produced a similar increase in blood pressure and heart rate, tolerance developed to the blood pressure effects of R (+)-Nornicotine, but not to the effects of S (−)-Nornicotine, across repeated treatments. Conclusion Both R (+)- and S (−)-Nornicotine may have potential utility as a novel tobacco use cessation agent.
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The pharmacological activity of nicotine and Nornicotine on nAChRs subtypes: relevance to nicotine dependence and drug discovery
Journal of neurochemistry, 2007Co-Authors: Roger L. Papke, Linda P Dwoskin, Peter A CrooksAbstract:Cigarette smoking and other forms of tobacco use deliver an array of pharmacologically active alkaloids, including nicotine and ultimately various metabolites of these substances. While Nornicotine is a significant component in tobacco as well as a minor systemic metabolite of nicotine, Nornicotine appears to be N-demethylated locally in the brain where it accumulates at relatively high levels after chronic nicotine administration. We have now examined the effects of Nornicotine on specific combinations of neuronal nicotinic acetylcholine receptor (nAChR) subunits expressed in Xenopus oocytes and compared these responses to those evoked by acetylcholine and nicotine. Of the nAChR subtypes studied, we have found that alpha7 receptors are very responsive to Nornicotine (EC50 approximately 17 micromol/L I(max) 50%, compared with acetylcholine (ACh)). nAChRs containing the ligand-binding domain of the alpha6 subunits (in the form of an alpha6/alpha3 chimera) are also strongly responsive to Nornicotine (EC50 approximately 4 micromol/L I(max) 50%, compared with ACh). Alpha7-type nAChRs have been suggested to be potential therapeutic targets for Alzheimer's disease, schizophrenia and possibly other pathologies. nAChRs containing alpha6 subunits have been suggested to have a role in nicotine-evoked dopamine release. Thus, understanding the actions of Nornicotine in the brain may have significance for both emerging therapeutics and the management of nicotine dependence.
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Nornicotine inhibition of dopamine transporter function in striatum via nicotinic receptor activation.
Synapse (New York N.Y.), 2007Co-Authors: Lisa S. Middleton, Peter A Crooks, Peter J. Wedlund, Wayne A. Cass, Linda P DwoskinAbstract:Nornicotine, a tobacco alkaloid and N-demethylated nicotine metabolite, releases DA from superfused rat striatal slices in a mecamylamine-sensitive manner, indicating nicotinic receptor (nAChR) modulation of this response. The current study determined the effect of Nornicotine on rat striatal dopamine transporter (DAT) function using in vivo voltammetry. In a dose-related and mecamylamine-sensitive manner, Nornicotine (0.35-12.0 mg/kg, s.c.) decreased DA clearance, suggesting that Nornicotine inhibits striatal DAT function via a nAChR-mediated mechanism. Furthermore, the nAChRs mediating the Nornicotine-induced inhibition of DAT function appear to be different from those activated by nicotine which increases DA clearance. Understanding the actions of Nornicotine in brain may have significance for emerging therapeutics and for the management of nicotine dependence.
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Effects of Nornicotine enantiomers on intravenous S(−)-nicotine self-administration and cardiovascular function in rats
Psychopharmacology, 2006Co-Authors: D. J. Stairs, Peter A Crooks, Linda P Dwoskin, N. M. Neugebauer, X. Wei, C. Boustany, M. Hojahmat, L. A. Cassis, M. T. BardoAbstract:Previous neurochemical evidence indicates that R(+)-Nornicotine is more potent than S(-)-Nornicotine in evoking dopamine release in rat nucleus accumbens slices. The current study tested the hypothesis that R(+)-Nornicotine is also more potent than S(-)-Nornicotine in selectively decreasing intravenous S(-)-nicotine self-administration in rats. After acute pretreatment (1-10 mg/kg for each enantiomer), R(+)-Nornicotine was more potent than S(-)-Nornicotine in decreasing S(-)-nicotine self-administration; in contrast, within the same dose range, the Nornicotine enantiomers were equipotent in decreasing sucrose-maintained responding. This enantioselectivity does not likely reflect a difference in bioavailability, since similar levels of Nornicotine were recovered from the brain 60 min after injection (5.6 mg/kg for each enantiomer). With repeated pretreatment, tolerance did not develop to the rate-decreasing effect of either Nornicotine enantiomer (3 or 5.6 mg/kg) with respect to the decrease in S(-)-nicotine self-administration, although the enantioselectivity dissipated across repeated pretreatments. While both enantiomers acutely produced a similar increase in blood pressure and heart rate, tolerance developed to the blood pressure effects of R(+)-Nornicotine, but not to the effects of S(-)-Nornicotine, across repeated treatments. Both R(+)- and S(-)-Nornicotine may have potential utility as a novel tobacco use cessation agent.
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effects of Nornicotine enantiomers on intravenous s nicotine self administration and cardiovascular function in rats
Psychopharmacology, 2006Co-Authors: D. J. Stairs, Peter A Crooks, Linda P Dwoskin, N. M. Neugebauer, X. Wei, C. Boustany, M. Hojahmat, L. A. Cassis, M. T. BardoAbstract:Rationale Previous neurochemical evidence indicates that R(+)-Nornicotine is more potent than S(−)-Nornicotine in evoking dopamine release in rat nucleus accumbens slices.
Kim D. Janda - One of the best experts on this subject based on the ideXlab platform.
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Nornicotine-organocatalyzed aqueous reduction of α,β-unsaturated aldehydes
Chemical communications (Cambridge England), 2007Co-Authors: Andrew P Brogan, Tobin J. Dickerson, Kim D. JandaAbstract:Nornicotine, a native component of tobacco and minor nicotine metabolite, was found to catalyze the chemoselective reduction of alpha,beta-unsaturated aldehydes under homogeneous aqueous conditions.
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Nornicotine organocatalyzed aqueous reduction of α β unsaturated aldehydes
Chemical Communications, 2007Co-Authors: Andrew P Brogan, Tobin J. Dickerson, Kim D. JandaAbstract:Nornicotine, a native component of tobacco and minor nicotinemetabolite, was found to catalyze the chemoselective reduction of α,β-unsaturated aldehydes under homogeneous aqueous conditions.
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Nornicotine aqueous aldol reactions: synthetic and theoretical investigations into the origins of catalysis.
The Journal of organic chemistry, 2004Co-Authors: Tobin J. Dickerson, Timothy Lovell, Michael M. Meijler, Louis Noodleman, Kim D. JandaAbstract:The recent discovery that Nornicotine 1, a minor nicotine metabolite, can catalyze the aldol reaction under physiologically relevant conditions has initiated research efforts into the potential chemical roles of nicotine metabolites. Herein, we disclose studies aimed at determining the origin and thus mechanism of the Nornicotine-catalyzed aqueous aldol reaction. Conformationally constrained compounds designed to mimic the low-energy conformations of Nornicotine were synthesized and tested for aldol catalysis; however, none showed rate enhancements on par with Nornicotine. To further explore the mechanism of this process, a density functional theory (DFT) study was performed by using a variety of compounds previously tested for catalysis. These in silico studies have uncovered an unprecedented mechanistic subtlety of aqueous aldol reactions. Unlike the single transition state model observed for aldol reactions in organic solvent, the Nornicotine-catalyzed reaction in water proceeds via a two-step mechanism in which a water molecule is utilized in both steps and a stable intermediate is generated. In total, these studies validate the proposed enamine-based mechanism of Nornicotine-catalyzed aqueous aldol reactions and also provide the basis for future studies into the stereoelectronic nature of individual catalyst structures.
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Glycation of the amyloid β-protein by a nicotine metabolite: A fortuitous chemical dynamic between smoking and Alzheimer's disease
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Tobin J. Dickerson, Kim D. JandaAbstract:The origin of Alzheimer's disease (AD) has been subjected to an intense amount of examination; however, a clear conclusion as to the nature of this crippling disease has yet to be identified. What is readily accepted is that a definitive marker of this disease is the aggregation of the amyloid β-peptide (Aβ) into neuritic plaques. The recent observation that nicotine exposure leads to delayed onset of AD has stimulated a flurry of research into the nature of this neuroprotective effect. This phenomenon has been debated, but no consensus has been reached, and although these studies have targeted nicotine, the primary alkaloid in tobacco, few studies have considered the physiological role of nicotine metabolites in disease states. Nornicotine is a major nicotine metabolite in the CNS and has been shown to participate in the aberrant glycation of proteins in vivo in a process termed Nornicotine-based glycation. Herein is detailed a potentially fortuitous role of Nornicotine-based glycation in relation to the pathology of AD. Specifically, Nornicotine was found to covalently alter Aβ, leading to reduced peptide aggregation. Potential consequences of this reaction cascade include reduced plaque formation and/or altered clearance of the peptide, as well as attenuated toxicity of soluble Aβ aggregates. The findings described provide an alternative mechanism for nicotine neuroprotection in AD and a means for the alteration of amyloid folding based on a covalent chemical event.
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A previously undescribed chemical link between smoking and metabolic disease.
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Tobin J. Dickerson, Kim D. JandaAbstract:Over the past 20 years, protein glycation has been implicated in a variety of pathological states. Although smoking also can contribute to many of these diseases, the precise mechanism by which this occurs is not known. Previously, we have demonstrated that Nornicotine, a constituent of tobacco and metabolite of nicotine, can catalyze aldol reactions under aqueous conditions. This finding has caused us to question whether this reaction has physiological consequences. We now report that Nornicotine causes aberrant protein glycation and catalyzes the covalent modification of certain prescription drugs such as the commonly used steroid, prednisone. Furthermore, we show that the plasma of smokers as compared with nonsmokers contains higher concentrations of Nornicotine-modified proteins, suggesting an unrecognized pathway for the development of the pathology of tobacco abuse.
Irina Stepanov - One of the best experts on this subject based on the ideXlab platform.
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Nornicotine nitrosation in saliva and its relation to endogenous synthesis of n nitrosoNornicotine in humans
Nicotine & Tobacco Research, 2013Co-Authors: Aleksandar Knezevich, Dorothy K. Hatsukami, Stephen S. Hecht, John Muzic, Irina StepanovAbstract:INTRODUCTION We recently reported that certain amounts of the carcinogen N'-nitrosoNornicotine (NNN) can be formed endogenously from nicotine and/or Nornicotine in some users of oral nicotine replacement therapy products. Although the acidic environment of the stomach creates the most favorable conditions for nitrosation, this reaction could also occur in the oral cavity in the presence of bacteria that catalyze nitrosation at neutral pH. METHODS To test the hypothesis that endogenous formation of NNN could occur in the oral cavity, we investigated nitrosation of nicotine and Nornicotine in human saliva. To specifically identify NNN as derived from precursors added to saliva, we incubated saliva samples with [pyridine-D(4)]nicotine and [pyridine-D(4)]Nornicotine, with and without the addition of nitrite, and subsequently analyzed [pyridine-D(4)]NNN by liquid chromatography-tandem mass spectrometry. RESULTS Consistent with kinetic studies on nicotine and Nornicotine nitrosation, incubation of saliva with [pyridine-D(4)]Nornicotine alone produced detectable amounts of [pyridine-D(4)]NNN, whereas only traces of [pyridine-D(4)]NNN were found in samples incubated with [pyridine-D(4)]nicotine and sodium nitrite. Incubation of saliva samples from 10 nonsmoking volunteers with [pyridine-D(4)]Nornicotine resulted in the formation of [pyridine-D(4)]NNN in 8 samples, with yields ranging from 0.003% to 0.051% of the added alkaloid. CONCLUSION Our results demonstrate that NNN can be formed from Nornicotine in human saliva without deliberate addition of any other substance. Therefore, Nornicotine, as present in tobacco or in nicotine replacement products, is a carcinogen precursor.
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Nornicotine nitrosation in saliva and its relation to endogenous synthesis of N'-nitrosoNornicotine in humans.
Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco, 2012Co-Authors: Aleksandar Knezevich, Dorothy K. Hatsukami, Stephen S. Hecht, John Muzic, Irina StepanovAbstract:We recently reported that certain amounts of the carcinogen N'-nitrosoNornicotine (NNN) can be formed endogenously from nicotine and/or Nornicotine in some users of oral nicotine replacement therapy products. Although the acidic environment of the stomach creates the most favorable conditions for nitrosation, this reaction could also occur in the oral cavity in the presence of bacteria that catalyze nitrosation at neutral pH. To test the hypothesis that endogenous formation of NNN could occur in the oral cavity, we investigated nitrosation of nicotine and Nornicotine in human saliva. To specifically identify NNN as derived from precursors added to saliva, we incubated saliva samples with [pyridine-D(4)]nicotine and [pyridine-D(4)]Nornicotine, with and without the addition of nitrite, and subsequently analyzed [pyridine-D(4)]NNN by liquid chromatography-tandem mass spectrometry. Consistent with kinetic studies on nicotine and Nornicotine nitrosation, incubation of saliva with [pyridine-D(4)]Nornicotine alone produced detectable amounts of [pyridine-D(4)]NNN, whereas only traces of [pyridine-D(4)]NNN were found in samples incubated with [pyridine-D(4)]nicotine and sodium nitrite. Incubation of saliva samples from 10 nonsmoking volunteers with [pyridine-D(4)]Nornicotine resulted in the formation of [pyridine-D(4)]NNN in 8 samples, with yields ranging from 0.003% to 0.051% of the added alkaloid. Our results demonstrate that NNN can be formed from Nornicotine in human saliva without deliberate addition of any other substance. Therefore, Nornicotine, as present in tobacco or in nicotine replacement products, is a carcinogen precursor.
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Abstract 4650: Nornicotine nitrosation in human saliva and its relation to endogenous formation of N′-nitrosoNornicotine in oral nicotine replacement therapy users
Epidemiology, 2011Co-Authors: Irina Stepanov, Dorothy K. Hatsukami, Aleksandar Knezevich, John Muzic, Stephen S. HechtAbstract:Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL We recently reported occasional significant increases in urinary biomarkers of the potent human carcinogen N′-nitrosoNornicotine (NNN) in some users of oral nicotine replacement therapy (NRT) products, such as nicotine gum or lozenge, compared with baseline smoking levels in the same subjects. We hypothesized that this is due to endogenous synthesis of NNN through the reaction of nicotine and/or Nornicotine that is metabolically formed from nicotine or originally present in NRT products, with nitrosating agents supplied by diet. While the acidic environment of the stomach creates the most favorable conditions for nitrosation, this reaction can also occur in the oral cavity in the presence of bacteria that catalyzes nitrosation at neutral pH. To test the hypothesis that endogenous formation of NNN can occur in the oral cavity of NRT users, we investigated nitrosation of nicotine and Nornicotine in human saliva. To specifically identify NNN as derived from the precursors added to saliva, we used [pyridine-D4]nicotine and [pyridine-D4]Nornicotine and subsequently analyzed [pyridine-D4]NNN by liquid chromatography-tandem mass spectrometry. Aliquots of pooled saliva from nonsmoking volunteers were incubated for 30 min at 37 °C with either [pyridine-D4]nicotine or [pyridine-D4]Nornicotine, in the presence of various concentrations of sodium nitrite. [Pyridine-D4]NNN was not detected in the blank saliva aliquot that was added as a negative control. Incubation of saliva with 50 ng of [pyridine-D4]Nornicotine alone produced 38 pg [pyridine-D4]NNN, or 0.08% yield. The aliquot incubated with 200 ng of [pyridine-D4]Nornicotine and 7 mg of sodium nitrite formed 5,503 pg of [pyridine-D4]NNN (nearly 150-fold increase). Only traces of [pyridine-D4]NNN were detected in samples incubated with [pyridine-D4]nicotine. These results are in agreement with kinetic studies on nicotine and Nornicotine nitrosation. To investigate the effect of natural inter-individual variations in salivary nitrite and/or oral microflora on the amount of orally synthesized NNN, saliva samples from 10 nonsmoking volunteers were incubated with deuterium-labelled nicotine and Nornicotine. Formation of [pyridine-D4]NNN was observed in 6 samples treated with [pyridine-D4]Nornicotine, with yields ranging from 0.001 to 0.037% of the added alkaloid. Trace amounts of [pyridine-D4]NNN were detected in some samples incubated with [pyridine-D4]nicotine. In summary, our results demonstrate that NNN can be formed in human saliva in the presence of Nornicotine, supporting the hypothesis that NNN can be synthesized endogenously in oral NRT users. Removal of Nornicotine from NRT products could improve the safety of these products. Additional studies are needed to evaluate the contribution of metabolically formed Nornicotine to the endogenous formation of NNN in oral NRT users. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4650. doi:10.1158/1538-7445.AM2011-4650
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abstract 4650 Nornicotine nitrosation in human saliva and its relation to endogenous formation of n nitrosoNornicotine in oral nicotine replacement therapy users
Cancer Research, 2011Co-Authors: Irina Stepanov, Dorothy K. Hatsukami, Aleksandar Knezevich, John Muzic, Stephen S. HechtAbstract:Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL We recently reported occasional significant increases in urinary biomarkers of the potent human carcinogen N′-nitrosoNornicotine (NNN) in some users of oral nicotine replacement therapy (NRT) products, such as nicotine gum or lozenge, compared with baseline smoking levels in the same subjects. We hypothesized that this is due to endogenous synthesis of NNN through the reaction of nicotine and/or Nornicotine that is metabolically formed from nicotine or originally present in NRT products, with nitrosating agents supplied by diet. While the acidic environment of the stomach creates the most favorable conditions for nitrosation, this reaction can also occur in the oral cavity in the presence of bacteria that catalyzes nitrosation at neutral pH. To test the hypothesis that endogenous formation of NNN can occur in the oral cavity of NRT users, we investigated nitrosation of nicotine and Nornicotine in human saliva. To specifically identify NNN as derived from the precursors added to saliva, we used [pyridine-D4]nicotine and [pyridine-D4]Nornicotine and subsequently analyzed [pyridine-D4]NNN by liquid chromatography-tandem mass spectrometry. Aliquots of pooled saliva from nonsmoking volunteers were incubated for 30 min at 37 °C with either [pyridine-D4]nicotine or [pyridine-D4]Nornicotine, in the presence of various concentrations of sodium nitrite. [Pyridine-D4]NNN was not detected in the blank saliva aliquot that was added as a negative control. Incubation of saliva with 50 ng of [pyridine-D4]Nornicotine alone produced 38 pg [pyridine-D4]NNN, or 0.08% yield. The aliquot incubated with 200 ng of [pyridine-D4]Nornicotine and 7 mg of sodium nitrite formed 5,503 pg of [pyridine-D4]NNN (nearly 150-fold increase). Only traces of [pyridine-D4]NNN were detected in samples incubated with [pyridine-D4]nicotine. These results are in agreement with kinetic studies on nicotine and Nornicotine nitrosation. To investigate the effect of natural inter-individual variations in salivary nitrite and/or oral microflora on the amount of orally synthesized NNN, saliva samples from 10 nonsmoking volunteers were incubated with deuterium-labelled nicotine and Nornicotine. Formation of [pyridine-D4]NNN was observed in 6 samples treated with [pyridine-D4]Nornicotine, with yields ranging from 0.001 to 0.037% of the added alkaloid. Trace amounts of [pyridine-D4]NNN were detected in some samples incubated with [pyridine-D4]nicotine. In summary, our results demonstrate that NNN can be formed in human saliva in the presence of Nornicotine, supporting the hypothesis that NNN can be synthesized endogenously in oral NRT users. Removal of Nornicotine from NRT products could improve the safety of these products. Additional studies are needed to evaluate the contribution of metabolically formed Nornicotine to the endogenous formation of NNN in oral NRT users. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4650. doi:10.1158/1538-7445.AM2011-4650
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Endogenous formation of N'-nitrosoNornicotine in F344 rats in the presence of some antioxidants and grape seed extract.
Journal of agricultural and food chemistry, 2007Co-Authors: Diana Porubin, Stephen S. Hecht, Maria Gonta, Irina StepanovAbstract:N'-NitrosoNornicotine (NNN) is one of the most abundant strong carcinogens in unburned tobacco and cigarette smoke and is classified by the International Agency for Research on Cancer as carcinogenic to humans. Human exposure to NNN mainly occurs upon use of tobacco products. It is also possible that additional amounts of NNN are formed endogenously. The goal of this study was to evaluate the inhibitory effect of some antioxidants, including ascorbic acid and grape seed extract (GSE), on endogenous NNN formation in rats treated with Nornicotine and sodium nitrite by gavage twice daily for 3 days. The study included four groups of rats: (1) negative control group A, to which no chemical was administered; (2) negative control group B, treated with Nornicotine alone (2.5 micromol per gavage); (3) positive control group, to which both Nornicotine (2.5 micromol per gavage) and sodium nitrite (7.5 micromol per gavage) were administered; and (4) rats treated with Nornicotine (2.5 micromol per gavage), inhibitor (7.5 or 37.5 micromol per gavage), and sodium nitrite (7.5 micromol per gavage). The mean (+/-SD) total amount of NNN in the 3-day urine of rats treated with both Nornicotine and sodium nitrite was 4.78 +/- 2.88 nmol. The order of inhibition of endogenous NNN formation in rats at the molar ratio [nitrite]:[inhibitor] 1:5 was as follows: ascorbic acid (91%) > dihydroxyfumaric acid (86%) approximately catechin (85%) > resveratrol (no inhibition). Treatment of rats with grape seed extract did not produce statistically significant inhibition of endogenous Nornicotine nitrosation. This is the first study that demonstrates endogenous NNN formation in rats treated with Nornicotine and sodium nitrite and effective inhibition of this process by ascorbic acid, dixydroxyfumaric acid, and catechin.
Tobin J. Dickerson - One of the best experts on this subject based on the ideXlab platform.
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Nornicotine-organocatalyzed aqueous reduction of α,β-unsaturated aldehydes
Chemical communications (Cambridge England), 2007Co-Authors: Andrew P Brogan, Tobin J. Dickerson, Kim D. JandaAbstract:Nornicotine, a native component of tobacco and minor nicotine metabolite, was found to catalyze the chemoselective reduction of alpha,beta-unsaturated aldehydes under homogeneous aqueous conditions.
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Nornicotine organocatalyzed aqueous reduction of α β unsaturated aldehydes
Chemical Communications, 2007Co-Authors: Andrew P Brogan, Tobin J. Dickerson, Kim D. JandaAbstract:Nornicotine, a native component of tobacco and minor nicotinemetabolite, was found to catalyze the chemoselective reduction of α,β-unsaturated aldehydes under homogeneous aqueous conditions.
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Nornicotine aqueous aldol reactions: synthetic and theoretical investigations into the origins of catalysis.
The Journal of organic chemistry, 2004Co-Authors: Tobin J. Dickerson, Timothy Lovell, Michael M. Meijler, Louis Noodleman, Kim D. JandaAbstract:The recent discovery that Nornicotine 1, a minor nicotine metabolite, can catalyze the aldol reaction under physiologically relevant conditions has initiated research efforts into the potential chemical roles of nicotine metabolites. Herein, we disclose studies aimed at determining the origin and thus mechanism of the Nornicotine-catalyzed aqueous aldol reaction. Conformationally constrained compounds designed to mimic the low-energy conformations of Nornicotine were synthesized and tested for aldol catalysis; however, none showed rate enhancements on par with Nornicotine. To further explore the mechanism of this process, a density functional theory (DFT) study was performed by using a variety of compounds previously tested for catalysis. These in silico studies have uncovered an unprecedented mechanistic subtlety of aqueous aldol reactions. Unlike the single transition state model observed for aldol reactions in organic solvent, the Nornicotine-catalyzed reaction in water proceeds via a two-step mechanism in which a water molecule is utilized in both steps and a stable intermediate is generated. In total, these studies validate the proposed enamine-based mechanism of Nornicotine-catalyzed aqueous aldol reactions and also provide the basis for future studies into the stereoelectronic nature of individual catalyst structures.
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Glycation of the amyloid β-protein by a nicotine metabolite: A fortuitous chemical dynamic between smoking and Alzheimer's disease
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Tobin J. Dickerson, Kim D. JandaAbstract:The origin of Alzheimer's disease (AD) has been subjected to an intense amount of examination; however, a clear conclusion as to the nature of this crippling disease has yet to be identified. What is readily accepted is that a definitive marker of this disease is the aggregation of the amyloid β-peptide (Aβ) into neuritic plaques. The recent observation that nicotine exposure leads to delayed onset of AD has stimulated a flurry of research into the nature of this neuroprotective effect. This phenomenon has been debated, but no consensus has been reached, and although these studies have targeted nicotine, the primary alkaloid in tobacco, few studies have considered the physiological role of nicotine metabolites in disease states. Nornicotine is a major nicotine metabolite in the CNS and has been shown to participate in the aberrant glycation of proteins in vivo in a process termed Nornicotine-based glycation. Herein is detailed a potentially fortuitous role of Nornicotine-based glycation in relation to the pathology of AD. Specifically, Nornicotine was found to covalently alter Aβ, leading to reduced peptide aggregation. Potential consequences of this reaction cascade include reduced plaque formation and/or altered clearance of the peptide, as well as attenuated toxicity of soluble Aβ aggregates. The findings described provide an alternative mechanism for nicotine neuroprotection in AD and a means for the alteration of amyloid folding based on a covalent chemical event.
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A previously undescribed chemical link between smoking and metabolic disease.
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Tobin J. Dickerson, Kim D. JandaAbstract:Over the past 20 years, protein glycation has been implicated in a variety of pathological states. Although smoking also can contribute to many of these diseases, the precise mechanism by which this occurs is not known. Previously, we have demonstrated that Nornicotine, a constituent of tobacco and metabolite of nicotine, can catalyze aldol reactions under aqueous conditions. This finding has caused us to question whether this reaction has physiological consequences. We now report that Nornicotine causes aberrant protein glycation and catalyzes the covalent modification of certain prescription drugs such as the commonly used steroid, prednisone. Furthermore, we show that the plasma of smokers as compared with nonsmokers contains higher concentrations of Nornicotine-modified proteins, suggesting an unrecognized pathway for the development of the pathology of tobacco abuse.
