Nicotine and Other Tobacco Alkaloids

Literature about the extensive degradation of nicotine is richer than that on the catabolism of any other alkaloid. In spite of that, it is not yet possible to give a clear-cut and concise review of definite, established pathways. 

Yoshida (1962) injected [ N]-labeled nicotine into Nicotiana tabacum at various stages of development and found that in young plants, up to 80% of the labeled nicotine was degraded during the 2 weeks after feeding. In older plants such degradation amounted to only 50% and in topped plants only 20% during the same period of time. The author did not study the 

During the air-curing of tobacco leaves, loss of nicotine decreased (27-52%) with leaf maturity, and the loss was accompanied by the familiar browning of the leaves during curing (Yoshida, 1971). 

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While cigarette sales in the USA declined 18%, from 21 billion packs in 2000 to 17.4 billion packs in 2007, during the same time period sales of other products, such as moist snuff, increased by 1.10 billion cigarette pack equivalents (Connolly and Alpert 2008). In the USA, the most common smokeless tobacco (ST) products are chewing tobacco (loose leaf, plug, and twist), moist snuff, and dry snuff. Many other forms of smokeless tobacco that are used globally were described in an lARC monograph (lARC 2007). All ST products contain nicotine and other tobacco alkaloids that are inherent to tobacco leaf. 

Table 2. Relative molar potency of nicotine and other tobacco alkaloids. 

Hecht, S.S. and A.R. Tricker Nitrosamines derived from nicotine and other tobacco alkaloids Chapter 11 in Analytical determination of nicotine and related compounds and their metabohtes, edited by J.W. Gorrod and P. lacob III, Elsevier, New York NY (1999) 421 88. Hecht, S.S., T.C. Tso, and D. Hoffmann Approaches to the reduction of nitrosamines and aromatic amines in Modifying the risk for the smoker. Proc. 3rd World Conf. on Smoking and Health, edited by E.L. Wynder, D. Hoffmann, and G.B. Gori, 1975, DHEW Publ. No. (NIH) 76-1221 (1976) 535-545. 

Schmeltz, L Nicotine and other tobacco alkaloids in Naturally occurring insecticides, edited by M. Jacobson and D.G. Crosby, Marcel Dekker, New York, NY (1971) pp. 99-136. 

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. 

Alkaloids and Phenols from Tobacco, Tomato, and Potato. Tobacco, tomato, and potato plants contain a number of toxic alkaloids. Probably the most widely studied Is nicotine. The Insecticidal properties of this and other tobacco alkaloids have been reviewed (72). A study of Nlcotlana showed that alkaloids are secreted by trlchomes In the seven species tested (73). Nicotine was the major alkaloid Identified In the trlchome secretion (7A). Anabaslne and nornlcotlne were also Identified In two species (75). Other ether soluable constitutents have also been Identified (76). Aphids were killed by contact with these secretions. Trlchome secretions from Nlcotlana also were... 

Nicotine and minor tobacco alkaloids are present in some foodstuffs and the environment (as environmental tobacco smoke), so that virtually everyone is exposed to these alkaloids, albeit at relatively low doses, for a long period of time. Ctinical s)unptoms associated with chronic toxicity due to exposure to nicotine alone or other minor tobacco alkaloids have not been reported in man. Until recently no long term study of low level nicotine exposure in relation to toxicity in man had been carried out and such observations that have been made were usually extrapolations from exposure to tobacco smoke or environmental tobacco smoke (ETS). This situation is changing with the widespread use of nicotine patches, chewing gum and nasal sprays in smoking cessation programmes. Eventually it may be possible to differentiate between the effects of nicotine and the numerous (over 3000) constituents of tobacco smoke. 

Approximately 40-60 mg of nicotine (43) is a lethal dose for an adult human the LD50 i.v. in mouse is 0.3 mg/kg (Wink, 1993). This base is the main pharmacologically active component of tobacco smoke and probably is responsible for the addictive nature of cigarettes. The pharmacology of nicotine and other Nicotiana alkaloids has been reviewed (Fodor and Colasanti, 1985). Nicotine mimics acetylcholine and activates acetylcholine receptors (Wink, 1993). 

For several years it was assumed that the putrescine, which forms a part of nicotine and other pyrrolidine alkaloids, arises through the action of ODC (Mizusaki et a/., 1973) and, in fact, pyrrolidine alkaloids have been classified as ornithine-derived compounds (Leete, 1980). In contrast, our investigations with tobacco callus tissue have shown that (1) changes in the ADC activity parallel changes in alkaloid levels, while changes in ODC activity do not (2) DFMA effectively inhibits the biosynthesis of nicotine and nomicotine, while DFMO is less effective and (3) the flow of from uniformly labeled arginine... 

The primary psychoactive alkaloid in tobacco is nicotine (figure 4.9), occuring between 0.6 and 9.0% (Robbers et al. 1996 Gruenwald et al. 1998). Other alkaloids include nornicotine, N-formylnornicotine, cotinine, myosmin, )S-nicotyrine, anabasine, and nicotellin. Nicotine alone can produce the effects commonly associated with tobacco use, but other tobacco alkaloids are likely to contribute. 

SAFETY PROFILE Tobaccos contain 0.5-5% alkaloids, predominantly as 1-nicotine (>85%). Nicotine is strongly addictive and is the chief cause of tobacco dependence. It is a mild stimulant. It readily forms salts with most acids. These salts are poorly absorbed through the mucous membranes, whereas the base is easily absorbed. This explains the practice of combining lime or other alkali in conjunction with ingestion tobacco use. Nicotine and some of the other tobacco alkaloids are experimental teratogens and mutagens. 

A new photometric determination of volatile bases in tobacco and tobacco smoke in terms of nicotine, which compares quantitatively with mass spectral and g.c. methods, has been developed.27 A colorimetric method for the estimation of nicotine alkaloids in tobacco by reaction with cyanogen bromide and 4,4 -di-aminostilbene-2,2 -disulphonic acid has also been reported.28 Dilute sulphuric acid extraction of nicotine and anabasine from autopsy tissue appears to be a more efficient method than extraction with acidified ethanol, aqueous oxalic acid, and steam distillation.29 Thin-layer chromatography has been effective in the analysis of nicotine and other alkaloids and drugs.30 Two reports on the isolation of anabasine from anabasine-lupinine mixtures have appeared.31 The P a values of some nicotine-type compounds have been determined.32... 

These alkaloids were mostly found in crude nicotine obtained commercially by treating the leaves of cultivated tobacco Nicotiana tabacum L. and sometimes N. rustica L.) with an aqueous solution of an alkali and distilling with steam (265). The total nicotine content of the tobacco plant is distributed as follows flowers, 5%, stems 18%, roots 13%, and leaves 64% (266). There is considerable variation in the nicotine content of different varieties of tobacco, but there is a close parallelism in the plant between nicotine and citric acid. Nicotine in the plant, however, is not always combined with an organic acid. The glucoside tabacilin yields glucose, nicotine, and other substances (267) when hydrolyzed while the tobacco glucoside tabacin yields nicotine when treated with alkalis (268). 

Based on the unusual adsorptive and decay characteristics of nicotine, some investigators are turning their attention to 3-ethenylpyridine as a tracer of ETS (Thome et al. 1986 Eatough et al. 1989b Ogden 1991). Second in concentration only to nicotine among the ETS alkaloids, 3-ethenylpyridine more nearly reflects the attributes of an ideal tracer discussed above than do any of the other tobacco alkaloids. 

All the available evidence suggests that plants make alkaloids to deter predators. Some, like the tobacco alkaloids are strongly toxic to insects. Nicotine, anabasine and other related alkaloids are produced in the roots of the tobacco plant and translocated to the leaves. Nicotine is certainly toxic to most insects. Formerly, a crude preparation of nicotine was used commercially as an insecticide, but the tobacco hornworm (Manduca sexto) (Plate 15) has adapted itself so that its larvae feed only on tobacco... 

In a further application of MI-SPE, theophylline could be separated from the structurally related caffeine by combining the specific extraction with pulsed elution, resulting in sharp baseline-separated peaks, which on the other hand was not possible when a theophylline imprinted polymer was used as stationary phase for HPLC. A detection limit of 120 ng mb1 was obtained, corresponding to a mass detection limit of only 2.4 ng [45]. This combination of techniques was also used for the determination of nicotine in tobacco. Nicotine is the main alkaloid in tobacco and is the focus of intensive HPLC or GC analyses due to its health risk to active and passive consumers. However, HPLC- and GC-techniques are time-consuming as well as expensive, due to the necessary pre-purification steps required because the sample matrices typically contain many other organic compounds besides nicotine. However, a simple pre-concentration step based on MI-SPE did allow faster determination of nicotine in tobacco samples. Mullett et al. obtained a detection limit of 1.8 jig ml 1 and a mass detection limit of 8.45 ng [95]. All these examples demonstrate the high potential of MI-SPE to become a broadly applicable sample pre-purification tool. 

The primary alkaloid in tobacco is nicotine, but tobacco also contains small amounts of minor alkaloids such as anabasine, anatabine, myosmine, and others. The minor alkaloids are absorbed systemically and can be measured in the urine of smokers and users of smokeless tobacco (Jacob et al. 1999). The measurement of minor alkaloids is a way to quantitate tobacco use when a person is also taking in pure nicotine from a nicotine medication or a nontobacco nicotine delivery system. This method has been used to assess tobacco abstinence in clinical trials of smoking cessation with treatment by nicotine medications (Jacob et al. 2002). 

Raw opium is harvested from the seed pod of the opium poppy. As many as 50 substances called alkaloids can then be derived from opium, and the opium can be further processed. Alkaloids are naturally occurring plant products that possess some pharmacological activity, and are found in other plants as well as opium poppies. Cocaine and nicotine are examples of alkaloids derived from the coca plant and the tobacco plant,... 

Although cotinine is one of the important tobacco alkaloids and is known as the first metabolite of nicotine in the human body, the conventional chemical methods for its synthesis from nicotine are not always satisfactory. On the other hand, the oxygenation of nicotine 60 to cotinine 61 by using the electroreduetively generated superoxide anion has been studied, since it has been mentioned that the anion may have a similar reactivity to the biological oxidation 41 The maximum yield (65.2%) was obtained when the electroreduction was carried out at —0.9 V in aerating DMF with a carbon rod anode. 

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