Tobacco smoke alkaloids

A. Bavley, and H. Wakeham Tobacco smoke alkaloids Isolation and identification of harmane Proc. 3rd Intemat. Tob. Sci. Cong., Salisbury, Rhodesia (1963) 550-556. Ponstein, A.S., S.A. Bres-Vloemans, M.B. Sela-Buurlage, P.J.M. van den Elzen, L.S. Melchers, and... 

The principal pyrolysis products of nicotine and related alkaloids are myosmine, nicotyrine, cotinine, bipyridine, and a series of simpler pyridine derivatives. Besides pyridine itself, the major derivatives are alkyl-substituted pyridines which include 3-ethenylpyridine, 3-picoline (along with the 2- and 4- isomers), and the various isometric lutidines (Kuhn 1965). Structures of the most important tobacco and tobacco smoke alkaloids are illustrated in Fig. 1. Because of the extreme dilution of ETS in most indoor environments, many of these alkaloids are virtually nondetectable in real-world settings. 

Tobacco and its alkaloids have long ceased to have any therapeutic importance, but their extensive use as insecticides and the demand for nicotine for the manufacture of nicotinic acid have stimulated interest in processes of extraction and methods of estimation. On the latter subject there is a voluminous literature, of which critical resumes have been published by various authors.Recent work on this subject has been specially concerned with (1) the development of miero- and semi-miero-methods suitable for estimating nieotine in tobacco smoke and the distribution of nieotine on sprayed garden produce, in treated soils and in tobaeeo leaves,(2) the study of conditions necessary to ensure satisfactory results in using particular processes, " and (3) methods of separation and estimation of nicotine, nomicotine and anabasine in mixtures of these bases. ) In the United States and in Russia considerable interest is being shown in the cultivation of types of tobacco rich in nicotine, in finding new industrial uses for tobacco and its alkaloids, and in possible by-products from tobacco plants such as citric and malic acids, i " Surveys of information on tobacco alkaloids have been published by Jackson, i Marion and Spath and Kuffner. ... 

Alkaloids of Tobacco Smoke. The following alkaloids, apart from normal alkaloidal constituents of tobacco, have been isolated by Wenusch and Schoeller from tobaceo smoke. 

Precursors and Formation. Tobaccos used for commercial products in the U.S.A, contain between 0,5 and 2,7% alkaloids. Nicotine constitutes 85-95% of the total alkaloids (14,26,27). Important minor alkaloids are nornicotine, anatabine, anabasine, cotinine and N -formylnornicotine (Figure 6), Several of these alkaloids are secondary and tertiary amines and, as such, amenable to N-nitrosation. The N-nitrosated alkaloids identified to date in tobacco and tobacco smoke include N -nitrosonornico-tine (NNN), 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone (NNK) and N -nitrosoanatabine (NAT Figure 7). In model experiments, nitrosation of nicotine also yielded 4-(methylnitrosamino)-4-(3-pyridyl)butanal (NNA 28). 

Nonvolatile Nitrosamines In Tobacco Smoke. Although there are more than 10 million exsmokers in the U.S.A., 53 million adults continue to smoke cigarettes and an additional 10 million still smoke cigars or pipes (39). The cigarette smokers are exposed to about 10 ng of volatile nitrosamines, 20-40 ng of NDELA and, most importantly, to 1-10 pg of tobacco specific N-nitros-amines with each cigarette smoked (Table IV). Similar quantities of the TSNA are found in sidestream smoke. The quantities of TSNA in the smoke are dependent on nitrate, nitrite, tobacco alkaloids and on NNN, NNK and NAT in the tobacco itself (31)>... 

This section focnses on the nse of nicotine and cotinine and other tobacco alkaloids as biomarkers of tobacco exposure. Other potential biomarkers of exposure to the particulate or gas phase of tobacco smoke are described in the review papers cited above. 

Leete E (1983) Biosynthesis and metabohsm of the tobacco alkaloids. In Pelletier SW (ed) Alkaloids chemical and biological perspectives, WUey, New York, pp 85-152 Leong JW, Dore ND, SheUey K, Holt EJ, Laing lA, Palmer LJ, LeSouef PN (1998) The elimination half-hfe of urinary cotinine in children of tobacco-smoking mothers, Pulm Pharmacol Ther ll(4) 287-290... 

The predominant alkaloid fonnd in tobacco is (—)-nicotine other molecnles found in tissnes of smokers are either present in tobacco smoke or are metabolites of nicotine, inclnding (4-)-nicotine, (-P)-nomicotine, (—)-nomicotine and (—)-cotinine, the major metabolite (Clark et al. 1965). In animals trained to recognise the stunnlns produced by (—)-nicotine, (-P)-nicotine fully substituted for (—)-nicotine but was about one-tenth as potent. There was no stereoselectivity in responding observed with the metabolite nomicotine and both (-p) and (—)-isomers fully substituted for nicotine but again were 10-fold less potent. (—)-Cotinine also substitnted for nicotine at very high doses bnt this conld be explained by the presence of small amounts of (—)-nicotine in the sample of cotinine (Goldberg et al. 1989). 

Relative to the conjugate acid AlkH+, the conjugate base Aik is free of the H+. Hence, Aik is frequently referred to as the free-base form of the alkaloid. Reaction 1 occurs readily in many environments including cellular cytoplasm, water, the particulate matter droplets of tobacco smoke, and blood serum. 

The most direct way to help people manage the symptoms of nicotine dependence and withdrawal is therapeutic use of nicotine replacement therapy (NRT) (Fiore et al. 2000 Henningfleld 1995 American Psychiatric Association 1996). Nicotine has been shown to be the main active ingredient in tobacco that causes and sustains addiction to tobacco (US Department of Health and Human Services 1988). Laboratory research has demonstrated that animals (Goldberg et al. 1983) and humans (Henningfleld et al. 1983) who have been chronically exposed to nicotine or tobacco smoke will self-administer nicotine infusions. It should be noted that other constituents in tobacco, such as MAO inhibitors (Fowler et al. 1996a, b), may also play a role in tobacco dependence. The potential role of alkaloids other than nicotine has not been ruled out. This is consistent with the observations that what has been termed tobacco delivered nicotine is more addictive and toxic than formulations provided by nicotine replacement medications (Royal College of Physicians 2000). 

Nicotine is well absorbed from the mucous membranes in the oral cavity, gastrointestinal tract, and respiratory system. If tobacco smoke is held in the mouth for 2 seconds, 66 to 77% of the nicotine in the smoke will be absorbed across the oral mucosa. If tobacco smoke is inhaled, approximately 90 to 98% of the nicotine will be absorbed. Nicotine is distributed throughout the body, readily crossing the blood-brain and placental barriers. The liver, kidney, and lung metabolize approximately 80 to 90% of the alkaloid. The kidney rapidly eliminates nicotine and its metabolites. 

Not surprisingly, therefore, 2,3 -bipyridine is an ingredient of tobacco smoke and is a constituent of tobacco liquors. " An alkaloid named iso-nicoteine, which was isolated from Turkish tobacco liquors and was thought to be a pyridylpyrrole derivative, was subsequently shown to be identical to 2,3 -bipyridine. 5-Methyl-2,3 -bipyridine, 2,2 -bipyridine, and 4,4 -bipyridine are also found in tobacco smoke. The range of bipyridines found in tobacco smoke condensate has been considerably extended with the identification of several alkyl substituted 2,2 -, 2,3 -, and 3,3 -bipyri-... 

Figure 1. Common tobacco alkaloids in tobacco and/or tobacco smoke...

The laboratory of the Government Chemist in London undertakes the analysis of tobacco smokes in order to produce league tables (Fig. 20) of the tar and nicotine content of all cigarette brands available in the UK, on behalf of the British government. In this context tar is defined as the total particulate matter present in the main-stream smoke (inhaled smoke), adjusted for its content of water and nicotine alkaloids. Nicotine is defined as the total nicotine-type alkaloids present in the mainstream smoke both are expressed in mg per cigarette. The tar and nicotine league tables are published every six months, and include details of approximately 130 brands of cigarette. 

A review entitled General Methods of Alkaloid Synthesis includes pyrrolidine, pyridine, and Sceletium alkaloids.1 Another summarizes nitrogen-containing compounds in tobacco and tobacco smoke, and includes some pyrroles, pyrrolidines, pyridines, and alkaloids related to nicotine.2... 

Anabasine, a minor tobacco alkaloid in plants of Anabasis aphylla, is found in trace amounts in tobacco smoke, and, like nicotine, is one of the earliest known insecticides. In maximum current generation studies anabasine is equivalent to ACh and appears to act at the a nicotinic ACh receptor. ISQ analogs of anabasine were prepared but no pharmacological activity was reported [33],... 

Quin2,3 was the first to apply gas chromatography for the analysis of nicotine alkaloids in tobacco smoke. He used three sets of conditions to analyse the many alkaloids present in a wide boiling range. 

Lyerly and Greene18 determined nicotine, menthol and some other non-alkaloidal constituents in tobacco smoke. Single cigarettes were smoked through a Cambrigde filter, and the filter... 

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