Skip to main content

The metabolic fate of the minor tobacco alkaloids

  • Chapter
Nicotine and Related Alkaloids

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).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

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.

    Article  CAS  Google Scholar 

  • Baker, J.T. and Sifniades, S. (1979) Synthesis and properties of pyrrolin-2-ones. J. Org. Chem., 44, 2798–800.

    Article  CAS  Google Scholar 

  • Batsch, H. and Montesano, R. (1984) Relevance of nitrosamines to human cancer. Carcinogenesis, 5, 1381–93.

    Article  Google Scholar 

  • 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.

    Google Scholar 

  • Benowitz, N.L. and Jacob, III, P. (1991) Nicotine metabolism in humans. Clin. Pharmacol. Ther., 50(4), 462–3.

    Article  PubMed  CAS  Google Scholar 

  • Bowman, E.R. and McKennis, Jr., H. (1962) Studies on the metabolism of (—)cotinine in the human. J. Pharmacol. Exp. Ther.135, 306–11.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • Brandange, S. and Lindblom, L. (1979) The enzyme ‘aldehyde oxidase’ is an iminium oxidase. Biochem. Biophys. Res. Comm., 91, 991–6.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Dagne, E. and Castagnoli, Jr., N. (1972a) Structure of hydroxycotinine, a nicotine metabolite. J. Med. Chem.15, 356–60.

    Article  CAS  Google Scholar 

  • Dagne, E. and Castagnoli, Jr., N. (1972b) Cotinine N-oxide, a new metabolite of nicotine. J. Med. Chem., 15, 840–1.

    Article  CAS  Google Scholar 

  • Dagne, E., Gruenke, L. and Castagnoli, jr. N. (1974) Deuterium isotope effects in the in vivometabolism of cotinine. J. Med. Chem., 17, 1330–3.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • Hoffman, D., Harly, N.H., Fisenne, I. et al. (1990) Carcinogenic agents in snuff. J. Nat. Cancer Inst., 76(3), 435–7.

    Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    CAS  Google Scholar 

  • Kyerematen, G.A., Morgan, M.L., Chattopadhyay, B. et al. (1991a) Nicotine metabolism in humans. Clin. Pharmacol. Ther., 50(4), 462–3.

    Google Scholar 

  • Kyerematen, G.A. and Vesell, E.S. (1991b) Metabolism of nicotine. Drug Metabolism Reviews, 23(1&2), 3–41.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • Leete, E. and Chedekel, M.R. (1974) Metabolism of nicotine in Nicotiana glauca. Phytochemistry, 13, 1853–9.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • McKennis, Jr., H., Turnbull, L.B., Bowman, E.R. et al. (1959) Demethylation of cotinine in vivo. J. Am. Chem. Soc., 81, 3951–4.

    Article  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Google Scholar 

  • Ortiz de Montellano, P.R. (Ed.) (1986) Cytochrome P450, Plenum Press, New York.

    Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Rashid, M.A., Nikolin, B. and Nikolin, A. (1983) Investigation of some analytical, biochemical and toxicological characteristics of hydroxycotinine. Folia Medica, 18, 17–27.

    Google Scholar 

  • Schmeltz, I. and Hoffmann, D. (1977) Nitrogen-containing compounds in tobacco and tobacco smoke. Chem. Rev., 77 (3), 295–311.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Shigenaga, M. (1989a) Studies on the metabolism and bioactivation of (S)-nicotine and ß-nicotyrine. Ph.D. Thesis, University of California, San Francisco.

    Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Stålhandske, T. (1970) The metabolism of nicotine and cotinine by mouse liver preparation. Acta Physiol. Scand., 78, 236–48.

    Article  PubMed  Google Scholar 

  • Stålhandske, T. and Slanina, P. (1982) Nicotyrine inhibits in vivometabolism of nicotine without increasing its toxicity. Toxicol. Appl. Pharmacol., 65, 366–72.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

Download references

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints 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

Publish with us

Policies and ethics