Nicotyrine inhibits in vivo metabolism of nicotine without increasing its toxicity

Stålhandske, Torbjörn; Slanina, Premysl

doi:10.1016/0041-008x(82)90382-9

Cited by 19 publications

(21 citation statements)

References 8 publications

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“…The results of the current study indicate that this phenomenon is not occurring in humans as the activity of CYP2A6 was not affected by 7-day nicotine dosing compared with placebo, and in previous studies 7-day tobacco abstinence (tobacco abstinence corresponds to placebo treatment in the current study) has been a sufficiently long time period to increase CYP2A6 activity [6]. b-Nicotyrine, a minor tobacco alkaloid, inhibits effectively human CYP2A6 in vitro and metabolism of nicotine in mice in vivo [25,26]. Thus, b-nicotyrine is one candidate for the search for the inhibiting compound of nicotine metabolism in tobacco smoke.…”

Section: Discussionmentioning

confidence: 92%

Effects of nicotine on cytochrome P450 2A6 and 2E1 activities

Hukkanen

Jacob

Peng

et al. 2010

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Smoking slows the metabolism of nicotine and accelerates the metabolism of chlorzoxazone.• Nicotine is a useful probe for phenotyping cytochrome P450 2A6 activity and chlorzoxazone is a frequently used probe for CYP2E1 activity.• The tobacco smoke constituents responsible for the reduced CYP2A6 and increased CYP2E1 activities are unknown. WHAT THIS PAPER ADDS• This study demonstrates that CYP2A6 and CYP2E1 activities are not affected by nicotine dosing.• High-dose nicotine treatment has a low potential of interaction with CYP2A6 and CYP2E1 substrates.• The mechanisms of tobacco smoke-elicited changes in CYP2A6 and CYP2E1 activities are yet to be determined. AIMSSmoking slows the metabolism of nicotine and accelerates the metabolism of chlorzoxazone, which are probe reactions for cytochrome P450 2A6 (CYP2A6) and CYP2E1 activities, respectively. We aimed to determine the role of nicotine in these metabolic effects of cigarette smoking. METHODSThe study had a single-blind, randomized, crossover two-arm design. Twelve healthy smokers were given two transdermal patches with 42-mg nicotine a day or placebo patches, each for 10 days. The subjects abstained from smoking during the study arms. Oral chlorzoxazone was given on day 7 and deuterium-labelled nicotine-d2 and cotinine-d4 infusion on day 8. RESULTSThere was no significant influence of transdermal nicotine administration on pharmacokinetic parameters of nicotine-d2 or on the formation of cotinine-d2. Nicotine decreased the volume of distribution (62.6 vs. 67.7 l, 95% confidence interval of the difference -9.7, -0.6, P = 0.047) of infused cotinine-d4. There were no significant differences in disposition kinetics of chlorzoxazone between the treatments. CONCLUSIONSCYP2A6 and CYP2E1 activities are not affected by nicotine. The tobacco smoke constituents responsible for the reduced CYP2A6 and increased CYP2E1 activities remain unknown.

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Section: Discussionmentioning

confidence: 92%

Effects of nicotine on cytochrome P450 2A6 and 2E1 activities

Hukkanen

Jacob

Peng

et al. 2010

Brit J Clinical Pharma

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“…Some EC liquids like the one used in the present study contain non-nicotine tobacco alkaloids, flavorants, and other compounds in an attempt to simulate cigarette smoking. These compounds could contribute to the reinforcing effects of ECs through peripheral sensory mechanisms (e.g., improved taste, “throat hit”; Evans and Hoffman, 2014), CNS mechanisms (e.g., activation of mesolimbic dopamine pathways, Dwoskin et al, 1993, 1995), pharmacokinetic mechanisms (e.g., altered nicotine metabolism, Kramlinger et al, 2012; Stalhandske and Slanina, 1982) or a combination of these factors. Elucidating the relative roles of these mechanisms requires study of multiple routes of administration.…”

Section: Discussionmentioning

confidence: 99%

Abuse liability assessment of an e-cigarette refill liquid using intracranial self-stimulation and self-administration models in rats

LeSage

Staley

Muelken

et al. 2016

Drug and Alcohol Dependence

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Background The popularity of electronic cigarettes (ECs) has increased dramatically despite their unknown health consequences. Because the abuse liability of ECs is one of the leading concerns of the Food and Drug Administration (FDA), models to assess it are urgently needed to inform FDA regulatory decisions regarding these products. The purpose of this study was to assess the relative abuse liability of an EC liquid compared to nicotine alone in rats. Because this EC liquid contains non-nicotine constituents that may enhance its abuse liability, we hypothesized that it would have greater abuse liability than nicotine alone. Methods Nicotine alone and nicotine dose-equivalent concentrations of EC liquid were compared in terms of their acute effects on intracranial self-stimulation (ICSS) thresholds, acquisition of self-administration, reinforcing efficacy (i.e., elasticity of demand), blockade of these behavioral effects by mecamylamine, nicotine pharmacokinetics and nicotinic acetylcholine receptor binding and activation. Results There were no significant differences between formulations on any measure, except that EC liquid produced less of an elevation in ICSS thresholds at high nicotine doses. Conclusions Collectively, these findings suggest that the relative abuse liability of this EC liquid is similar to that of nicotine alone in terms of its reinforcing and reinforcement-enhancing effects, but that it may have less aversive/anhedonic effects at high doses. The present methods may be useful for assessing the abuse liability of other ECs to inform potential FDA regulation of those products.

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“…Since epoxides are electrophilic compounds capable of alkylating biomacromolecules, this pathway could have toxicological significance. It is interesting to note that nicotyrine inhibits the metabolism of nicotine in mice in vivo, resulting in higher nicotine tissue levels, without increasing its toxicity (Stalhandske and Slanina, 1982). Nicotyrine also inhibits human CYP2A6 enzyme in vitro (Denton et al, 2004).…”

Section: Metabolism Of Minor Alkaloids Of Tobaccomentioning

confidence: 99%