Abstract
This chapter is concerned with the metabolic fates of the so-called minor tobacco alkaloids. Nicotine*; (1, see Figure 7.1) is the most abundant (Schmeltz and Hoffman, 1977) and pharmacologically potent (Clark et al., 1965) alkaloid present in commercial tobacco products but is only one of a complex mixture of tobacco alkaloids. When considering the potential health consequences of exposure to tobacco products, it may be as well to remember that about 2200 components have been separated from tobacco plant extracts (Schmeltz and Hoffman, 1977) and almost 500 compounds in tobacco smoke have been characterized by gas chromatographic techniques (Schumacher et al., 1977).
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Andersen, R.A., Fleming, P.D., Burton, H.R. et al.(1991) Nitrosated, acylated, and oxidized pyridine alkaloids during storage of smokeless tobaccos: Effects of moisture, temperature, and their interactions. J. Agric. Food Chem., 39, 1280–87.
Baker, J.T. and Sifniades, S. (1979) Synthesis and properties of pyrrolin-2-ones. J. Org. Chem., 44, 2798–800.
Batsch, H. and Montesano, R. (1984) Relevance of nitrosamines to human cancer. Carcinogenesis, 5, 1381–93.
Beckett, A.H., Gorrod, J.W. and Jenner, P. (1972) A possible relation between pKa1 and lipid solubility and the amounts excreted in urine of some tobacco alkaloids given to man. J. Pharm. Pharmacol., 23, 555–615.
Benowitz, N.L. and Jacob, III, P. (1991) Nicotine metabolism in humans. Clin. Pharmacol. Ther., 50(4), 462–3.
Bowman, E.R. and McKennis, Jr., H. (1962) Studies on the metabolism of (—)cotinine in the human. J. Pharmacol. Exp. Ther.135, 306–11.
Bowman, E.R., Hanson, E., Turnbull, L.B. et al.(1964) Disposition and fate of (—)-cotinine-H3 in the mouse. J. Pharmacol. Exp. Ther., 143, 301–8.
Brandange, S. and Lindblom, L. (1979) The enzyme ‘aldehyde oxidase’ is an iminium oxidase. Biochem. Biophys. Res. Comm., 91, 991–6.
Caldwell, W.S., Green, J.M., Byrd, G.D. et al (1992)Characterization of the glucoronide conjugate of cotinine - A previously unidentified major metabolite of nicotine in smoker’s urine. Chem. Res. in Toxicol, 5, 280–5.
Clark, M.S.G., Rand, M.J. and Vanov, S. (1965) Comparison of pharmacological activity of nicotine and related alkaloids occurring in cigarette smoke. Arch. Int. Pharmacodyn., 156(2), 363–78.
Cundy, K.C. and Crooks, P.A. (1987) Biotransformation of primary nicotine metabolites II. Metabolism of [3Н]-5-(—)-cotinine in the guinea pig: determination of in vivourinary metabolites by high-performance liquid radio-chromatography. Xenobiotica, 17 (7), 785–92.
Dagne, E. and Castagnoli, Jr., N. (1972a) Structure of hydroxycotinine, a nicotine metabolite. J. Med. Chem.15, 356–60.
Dagne, E. and Castagnoli, Jr., N. (1972b) Cotinine N-oxide, a new metabolite of nicotine. J. Med. Chem., 15, 840–1.
Dagne, E., Gruenke, L. and Castagnoli, jr. N. (1974) Deuterium isotope effects in the in vivometabolism of cotinine. J. Med. Chem., 17, 1330–3.
Desai, D.H and Amin, S. (1991) Synthesis of a hapten to be used in development of immunoassays for trans-3’-hydroxycotinine, a major metabolite fo cotinine. Chem. Res. in Toxicol, 4, 524–7.
Djordjevic, M.V., Brynnemann, K.D. and Hoffmann, D. (1989) Identification and analysis of a nicotine-derived N-nitrosamine acid and other nitrosamino acids in tobacco. Carcinogenesis, 10(9), 1725–31.
Foth, H., Aubrecht, J., Home, M. et al.(1992) Increased cotinine elimination and cotinine-N-oxide formation by phenobarbital induction in rat and mouse. Clinical Investigator, 70, 175–81.
Frankenburg, W.G. and Vaitekunas, A.A. (1957) The chemistry of tobacco fermentation. I. Conversion of the alkaloids. D. Identification of cotinine in fermented leaves. J. Am. Chem. Soc., 79, 149–51.
Gorrod, J.W. and Hibberd, A.R. (1982) The metabolism of nicotine △1’(5’) iminiumion, in vivoand in vitro. Eur. J. Drug Metab. Pharmacokin., 7, 293–8.
Gorrod, J.W. and Jenner, P. (1975) The metabolism of tobacco alkaloids, in Essays in Toxicology, Vol. 6, Academic Press, New York, pp. 35–78.
Harke, H.-P., Schaller, D., Frahm, B., et al.(1974) Demethylation of nicotine and cotinine in pigs. Res. Comm. Chem. Path. Pharmacol., 9 (4), 595–9.
Hawkins, D.R. (Ed.) (1989) Biotransformation. A survey of the biotransformations of drugs and chemicals in animals, Vol. 2, The Royal Society of Chemistry, Cambridge (England), pp. 310–11.
Hibberd, A.R. and Gorrod, J.W. (1981) Nicotine Δ1’ (5’),in’inium ion: a reactive intermediate in nicotine metabolism. Adv. Exp. Med. Biol., 136 (Part B), 1121–31.
Hibberd, A.R. and Gorrod, J.W. (1985) Comparative N-oxidation of nicotine and cotinine by hepatic microsomes, in Biological Oxidation of Nitrogen in Organic Molecules, (Eds J.W. Gorrod and L.A. Damani) Ellis Norwood, Chichester (England), pp. 246–50.
Hill, D.L., Laster, Jr., W.R. and Struck, R.F. (1972) Enzymatic metabolism of cyclophosphamide and nicotine and production of a toxic cyclophosphamide metabolite. Cancer Res., 32, 658–65.
Hoffman, D., Harly, N.H., Fisenne, I. et al. (1990) Carcinogenic agents in snuff. J. Nat. Cancer Inst., 76(3), 435–7.
Jacob, III, P., Benowitz, N.L. and Shulgin, A.T. (1988) Recent studies of nicotine metabolism in humans. Pharmacol., Biochem. and Behavior, 30, 249–53.
Jacob, III, P., Shulgin, A.T. and Benowitz, N.L. (1990) Synthesis of (3’R, 5’S)trans-3’-hydroxycotinine, a major metabolite of nicotine. Metabolic formation of 3’-hydroxycotinine in humans is highly stereoselective. J. Med. Chem., 33, 1888–91.
Janzen, E.G. and Haire, D.L. (1990) Two decades of spin trapping, in Advances in Free Radical Chemistry, Vol. 1, ( Ed. D. Tanner) JAI Press Inc., Greenwich, Connecticut, pp. 253–95.
Jenner, P. and Gorrod, J.W. (1973) Comparative in vitro hepatic metabolism of some tertiary N-methyl tobacco alkaloids in various species. Res. Comm. Chem. Pathol. Pharmacol., 6(3), 829–43.
Kyerematen, G.A., Morgan, M.L., Chattopadhyay, B. et al. (1991a) Nicotine metabolism in humans. Clin. Pharmacol. Ther., 50(4), 462–3.
Kyerematen, G.A. and Vesell, E.S. (1991b) Metabolism of nicotine. Drug Metabolism Reviews, 23(1&2), 3–41.
Kyerematen, G.A., Morgan, M. and Chattopadhyay, B. et al.(1990) Disposition of nicotine and eight metabolites in smokers and nonsmokers: Identification in smokers of two metabolites that are longer lived than cotinine. Clin. Pharmacol. Ther., 48 (6), 641–51.
Kyerematen, G.A., Taylor, L.H., deBethizy, J.D. et al.(1987) Radiometric-highperformance liquid chromatographic assay for nicotine and twelve of its metabolites. J. Chromatog., 419, 191–203.
Kyerematen, G.A., Taylor, L.H., deBethizy, J.D. et al.(1988) Pharmаcokinetics of nicotine and 12 metabolites in the rat. Drug Metabol. Dispos., 16, 125–9.
Leete, E. and Chedekel, M.R. (1974) Metabolism of nicotine in Nicotiana glauca. Phytochemistry, 13, 1853–9.
McKennis, Jr., H., Schwartz, S.L., Turnbull, L.B. et al.(1962) The corrected structure of ketoamide arising from the metabolism of (—)-nicotine. J. Am. Chem. Soc., 84, 4598–9.
McKennis, Jr., H., Turnbull, L.B., Bowman, E.R. et al. (1959) Demethylation of cotinine in vivo. J. Am. Chem. Soc., 81, 3951–4.
Murphy, P.J. (1973) Enzymatic oxidation of nicotine to nicotine-A1,(5) iminium ion. A newly discovered intermediate in the metabolism of nicotine. J. Biol. Chem., 248, 2796–800.
Neurath, G.B., Dunger, M. Orth, D. et al.(1987) Trans-3’-hydroxycotinine as a main metabolite in urine of smokers. Int. Arch. Occup. Environ. Health, 59, 199–201.
Nguyen, T.-L., Dagne, E., Gruenke, L. et al.(1981) The tautomeric structures of 5-hydroxycotinine, a secondary mammalian metabolite of nicotine. J. Org. Chem., 46, 758–60.
O’Doherty, S., Revans, A., Smith, C.L. et al.(1988) Determination of cis-and trans-3-hydroxycotinine by high performance liquid chromatography. J. High Resol. Chromatog. & Chromatog. Comm., 11, 723–5.
Obach, R.S. and Van Vunakis, H. (1990) Nicotinamide adenine dinucleotide (NAD)-dependent oxidation of nicotine-A1 (5 -iminium ion to cotinine by rabbit liver microsomes. Biochem. Pharmacol., 39(1), R1–R4.
Ortiz de Montellano, P.R. (Ed.) (1986) Cytochrome P450, Plenum Press, New York.
Peterson, L.A. and Castagnoli, Jr., N. (1988) Regio-and stereochemical studies on the a-carbon oxidation of (5)-nicotine by cyctochrome P450 model systems. J. Med. Chem., 31, 637–40.
Rashid, M.A., Nikolin, B. and Nikolin, A. (1983) Investigation of some analytical, biochemical and toxicological characteristics of hydroxycotinine. Folia Medica, 18, 17–27.
Schmeltz, I. and Hoffmann, D. (1977) Nitrogen-containing compounds in tobacco and tobacco smoke. Chem. Rev., 77 (3), 295–311.
Schumacher, J.N., Green, C.R., Best, F.W. et al.(1977) Smoke composition. An extensive investigation of the water-soluble portion of cigarette smoke. J Agricultural Food Chem., 25 (2), 310–5.
Shigenaga, M. (1989a) Studies on the metabolism and bioactivation of (S)-nicotine and ß-nicotyrine. Ph.D. Thesis, University of California, San Francisco.
Shigenaga, M.K., Kim, B.H., Caldera-Munoz, P. et al.(1989b) Liver and lung microsomal metabolism of the tobacco alkaloid ß-nicotyrine. Chem. I Res. Toxicol., 2, 282–7.
Shulgin, A.T., Jacob, III, P., Benowitz, N.L. et al.(1987) Identification and quantitative analysis of cotinine-N-oxide in human urine. J. Chromatog., Biomed. Applications, 423, 365–72.
Stålhandske, T. (1970) The metabolism of nicotine and cotinine by mouse liver preparation. Acta Physiol. Scand., 78, 236–48.
Stålhandske, T. and Slanina, P. (1982) Nicotyrine inhibits in vivometabolism of nicotine without increasing its toxicity. Toxicol. Appl. Pharmacol., 65, 366–72.
Voncken, P., Schepers, G. and Schafer, K.H. (1989) Capillary gas chromato-graphic determination of trans-3’-hydroxycotinine simultaneously with nicotine and cotinine in urine and blood samples. J. Chromatog., 479, 410–8.
Wada, E. Bowman, E., Turnbull, L.B. et al.(1961) Norcotinine (desmethylcotinine) as a urinary metabolite of nornicotine. J. Med. Pharmacol. Chem., 4 (1), 21–30.
Yamada, S., Sakai, T. and Ohashi, M. (1986) A model reaction of nicotine metabolism-photo-induced electron transfer oxidation of nicotine. Photomedicine & Photobiology, 8 (2), 19–20.
Zhang, Y., Jacob, III, P. and Benowitz, N.D. (1990) Determination of nornicotine in smokers’ urine by gas chromatography following reductive alkylation to N’-propylnornicotine. J. Chromatog., 525, 349–57.
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1993 Springer Science+Business Media Dordrecht
About this chapter
Cite this chapter
Liu, X., Jacob, P., Castagnoli, N. (1993). The metabolic fate of the minor tobacco alkaloids. In: Gorrod, J.W., Wahren, J. (eds) Nicotine and Related Alkaloids. Springer, Dordrecht. https://doi.org/10.1007/978-94-011-2110-1_7
Download citation
DOI: https://doi.org/10.1007/978-94-011-2110-1_7
Publisher Name: Springer, Dordrecht
Print ISBN: 978-94-010-4936-8
Online ISBN: 978-94-011-2110-1
eBook Packages: Springer Book Archive