Tobacco-related alkaloids

A listing of the tobacco alkaloids is well beyond the scope of this chapter (see Chaps. 7 and 8) and would serve no useful purpose in the context of the present topic. Several reviews and historical surveys are cited for the interested reader (Kuhn 1965 Pailer 1965 Wynder and Hoffmann 1967 Stedman 1968 Leete 1983). In this chapter, all discussion will be restricted to the most abundant pyridine alkaloids in tobacco and selected 3-pyridyl derivatives formed on combustion. 

Alkaloids constitute approximately 2-4% by weight of fresh cigarette tobaccos (Kuhn 1965), with nicotine constituting roughly 95% of the total alkaloid fraction. The predominant secondary alkaloids, along with approximate percentages by weight of the alkaloid fraction, include anatabine (2-3%), nornicotine (1%), anabasine (0.5%), and myosmine (0.1%) (Kuhn 1965 Leete 1983). 

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An understanding of the pharmacology of nicotine and how nicotine produces addiction and influences smoking behavior provides a necessary basis for therapeutic advances in smoking cessation interventions. This chapter provides a review of several aspects of the human pharmacology of nicotine. These include the presence and levels of nicotine and related alkaloids in tobacco products, the absorption of nicotine from tobacco products and nicotine medications, the distribution of nicotine in body tissues, the metabolism and renal excretion of nicotine, nicotine and cotinine blood levels during tobacco use or nicotine replacement therapy, and biomarkers of nicotine exposure. For more details and references on the pharmacokinetics and metabolism of nicotine, the reader is referred to Hukkanen et al. (2005c). 

A series of reviews describing nicotine metabolism has recently appeared [2], Specific topics covered include the biosynthesis and metabolism of nicotine and related alkaloids [3], an overview of mammalian nicotine metabolism [4], the role of cytochrome P450 in nicotine metabolism [5], nicotine metabolism beyond cotinine [6], N-oxidation, A -methylation, and N-conjugation reactions of nicotine [7], extrahepatic metabolism of nicotine and related compounds [8], metabolism of the minor tobacco alkaloids [9], analysis and levels of nicotine and metabolites in body fluids [10], kinetics of nicotine and its metabolites in animals [11], pharmacokinetics of (S)-nicotine and metabolites in humans [12], and sources of inter-individual variation in nicotine pharmacokinetics [13]. Another recent review described variables which affect nicotine metabolism [14]. Several compilations of studies or reviews on the tobacco-specific A-nitrosamines are available [15-18]... 

Figure 2. Biosynthesis of tobacco alkaloids. (A) Formation of nicotinic acid, (B) formation of N-methyl-A -pyrroliniumion, and (C) condensation to produce tobacco alkaloids. Constructed from data of Bush LP, Fannin FF, Chelvarajan RL and Burton HR (1993). In Gorrod JW and Wahren J (eds.) Nicotine and Related Alkaloids Absorption, Distribution, Metabolism and Excretion. Chapman Hall, London, UK.

Because of the multitude of nicotine-related alkaloids, amino acids, and proteins in tobacco, diligent research eventually led to the identification of a host of alkyl amines in tobacco and smoke. In addition to ammonia, the only alkylamine listed as a tobacco smoke component in 1954 by Kosak (2170) was methylamine, but he questioned its identification even though he cited the 1904 report by Thoms (3912) and the 1930 report by Koperina (2161) on its identification. 

Nicotine (as well as the other nicotine-related alkaloids in tobacco, usually present in trace amounts) is the one tobacco component whose level in tobacco is sometimes controlled by removal in a denicotinization process. In contrast to the removal or reduction of its level in the case of nicotine, materials such as simple sugars, glycerol, and some flavorants are added to the tobacco blend to augment their existing levels in the tobacco and to enhance certain consumer acceptable organoleptic properties of the MSS. Materials such as... 

Precursors of NNAs in both tobacco and tobacco smoke are the proteins and amino acids (plus nitrate) for the volatile NNAs [Bmnnemann etal. (481, 482), Hoffmann etal. (1694)] and nicotine and nicotine-related alkaloids (plus nitrate) for the TSNAs [Boyland etal. (422, 423), Rathkamp etal. (3080), Hecht etal. (1563,1565)]. The levels of NNAs in tobacco and its smoke parallel the tobacco nitrate level [Morie and Sloan (2635), Hecht etal. (1576,1578), Tsoetal. (3985)]. 

Recent intensive interest in the physiological effects of habitual smoking has resulted in the publication of thorough reviews of the chemistry of tobacco constituents 76, 77). The chemistry of nicotine and related alkaloids including biosynthetic aspects has been surveyed 78) and the chemistry of pyrolysis products of tobacco alkaloids in smoke has been reviewed (79). 

Interest in alkaloids of the nicotine group appears to be on the increase. A review has appeared covering tobacco-specific nitrosamines, which may be causative factors in tobacco-related cancers. The solution conformation, and proton, deuterium, carbon-13, and nitrogen-15 n.m.r. spectra of nicotine and its 2- and 4-isomers, have been studied. A new synthesis of nornicotine and nicotine has been described, and a quantitative carbon-13 n.m.r. spectral analysis of nicotine that is labelled at positions 1, 2, and 3 with carbon-13 been presented. The synthesis and mass spectrometry of several structurally related nicotinoids have been reported. Nicotine is dehydrogenated on irradiation in benzene solution in the presence of benzophenone to l -methyl-2 -(3-pyri-dyl)pyrrole. ° Nornicotine has been synthesized in four steps from 3-bromo-pyridine and N-3-butenyl-phthalimide, using a palladium-catalysed vinylic... 

Nitrite content is important in the assessment of tobacco and alkaloids during storage and postharvest treatments because it is related to nitro-samine accumulation and bacterial activity. A colorimetric method for nitrite in tobacco samples has been developed that stabilizes and decolorizes leaf extracts for automated continuous flow analysis at ppb or greater (Crutchfield and Burton 1989). It avoids the problem that nitrite measurement in unsterilized tissue is error-prone because of bacteria-mediated reduction of nitrate to nitrite. The manifold arrangement is in Fig. 3. 

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. 

Nicotine is by far the most commonly used indicator of ETS in indoor air. Many authors state erroneously that nicotine is unique to tobacco however, such is not the case. Although present in a surprisingly large number of species other than Nicotiana (Leete 1983), and also detected at trace levels in a variety of common foods (Castro and Monji 1986 Sheen 1988 Davis et al. 1991), the presence of nicotine in indoor air should be uniquely attributable to tobacco smoke. The same should also hold true for the related alkaloids and the more unique pyrolysates (e.g., myosmine and 3 ethenylpyridine). 

Pailer M (1965) Chemistry of nicotine and related alkaloids (including biosynthetic aspects). In von Euler US (ed) Tobacco alkaloids and related compounds proc fourth int symp held at the Wenner-Gren center, vol 4. Stockholm, February 1964. Macmillan, New York, pp 15-36... 

Tobacco is derived from the leaves of Nicotiana tabacum (Solanaceae), and it was used to treat headache and toothache. However, it is not used as a medicine now, and smoking tobacco is now a global addictive habit. Tobacco leaf contains a large amount of nicotine (2-8%), and the nicotine extracted as nicotine sulfate is used as an insecticide in agriculture. Tobacco leaf contains more than ten related alkaloids other than nicotine, and all of these alkaloids possess a pyridine skeleton with 3-substitution. The main alkaloids other than nicotine, anabasine and nor-nicotine, are isolated from the leaf material, and these alkaloids also possess insecticidal activity. 

Denton TT, Zhang X, Cashman JR (2004) Nicotine-related alkaloids and metabolites as inhibitors of human cytochrome P-450 2A6. Biochem Pharmacol 67 751-756 Dinkel M, Bedner M (2001) Der Biorausch - ein neuer Trend. Notarzt 17 105-107 Djordjevic MV, Bush LP, Gay SL, Burton HR (1990) Accumulation and distribution of acylated nomicotine derivatives in flue-cured tobacco alkaloid isoUnes. J Agric Food Chem 38 347-350... 

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... 

There are four broad classes of alkaloids whose general economic aspects are important (/) the opiates such as morphine and codeine (2, R = H and R = CH3, respectively) (2) cocaine (11) (both Hcit and iUicit) (2) caffeine (16) and related bases in coffee and tea, and (4) the tobacco alkaloids such as nicotine (21). 

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. 

Lobelia or Indian tobacco consists of the dried leaves and tops of Lobelia inflata (Campanulaceae), an annual herb from the USA and Canada. Lobelia contains about 0.2-0.4% of alkaloids, of which the piperidine derivative lobeline (Figure 6.23) is the chief constituent. Minor alkaloids identified include closely related structures, e.g. lobelanine (Figure 6.23). The North American Indians employed lobelia as an alternative or substitute for tobacco (Nicotiana tabacum Solanaceae), and it is found that lobeline stimulates nicotinic receptor sites in a similar way to nicotine, but with a weaker effect. Lobeline has been employed in preparations intended as smoking deterrents. The crude plant drug has also long been used to relieve asthma and bronchitis, though in large doses it can be quite toxic. 

Pyrrolidine occurs free in small quantities in tobacco and opium and is related to its mother substance pyrrole (Figure 11.2). To this group belong such alkaloids as hygrine from Erythroxylon coca and stachydrine from Stachys tuberifera (Figure 11.3). 

Hodgson, E., Smith, E., and Guthrie, F.E., Two-dimensional thin-layer chromatography of tobacco alkaloids and related compounds, J. Chromatogr., 20, 176, 1965 Chem. Abs., 64, 3960b, 1966. 

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