Abstract
It has long been known that nicotine is metabolized to the corresponding amide cotinine (McKennis et al., 1957). The metabolism of nicotine has been investigated extensively (see Gorrod and Jenner, 1975; Nakayama, 1988). It has been suggested that the enzymatic formation of cotinine occurred via an intermediate (Hucker et al., 1960), which was then metabolized by “aldehyde” oxidase or “iminium oxidase” to form cotinine (Brandange and Lindblom, 1979; Hibberd and Gorrod, 1980). Evidence of a reactive intermediate probably from the cytochrome P-450 dependent oxidation of nicotine, was achieved when a stable product, identified as 5′-cyanonicotine was formed when cyanide was present during the metabolism (Murphy, 1973). This observation led Murphy (1973) to propose nicotine ∆l ′(5′) iminium ion as the reactive intermediate. To determine the site of enzyme activity responsible for the production of this reactive intermediate, experiments were carried out as in the original work by Hucker et al. (1960), and Booth and Boyland, (1971). Incorporation of radioactivity from 14C-cyanide by the substrate was examined by various cell fractions, i.e. isolated microsomes, and 140,000g soluble fraction. The metabolism of nicotine has been studied in many species. Miller and Larson, (1953) observed its metabolism by tissue slices from mouse, rabbit, rat, and dog. Enzymic oxidation of nicotine has also been observed in guinea pig (Booth and Boyland, 1971), and rabbit (Hucker et al., 1960). It was therefore decided to investigate the in vitro metabolism of nicotine to the cyanonicotine adduct by different mammalian laboratory species.
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References
Albert, A., Serjeant, E.P. (1971). The determination of ionization constants: A Laboraotry Manual, 2nd Ed. Chapman and Hall.
Beckett, A.H., Shenoy, E.V.R. (1973). The effect of N-alkyl chain length and stereochemistry on the absorption, metabolism and urinary excretion of Nalkylamphetamines in man. J. Pharm. Pharmacol. 25, 793.
Booth, J., Boyland, C. (1971). Enzymic oxidation of (-)nicotine by guinea pig tissues in vitro. Biochem. Pharmacol. 20, 407–415.
Brandange, S., Lindblom, L. (1979). The enzyme ‘aldehyde oxidase’ is an iminium oxidase. reaction with nicotine Al t(51) iminium ion. Biochem. Biophys. Res. Commun. 91, 991–996.
Caddy, B., Idowu, R., Tilstone, W.J., and Thomson, N.C. (1980). Analysis and disposition of dextromoramide in body fluids. Forensic toxicology. Proceedings of the European meeting of the International Association of Forensic Toxicologists. Ed. J. Oliver. Croom Helm, London, p 126.
Case, D.E. and Reeves, P.R. (1975). The dispisition and metabolism of I.C.I. 58,834 (viloxazine) in humans. Xenobiotica 5, 113–129.
Chiba, K., Peterson, L.A., Castagnoli, K.P., Trevor, A.J. and Castagnoli, Jr., N. (1985). Studies on the molecular mechanism of bioactivation of the selective nigrostriatal toxin 1-methy1–4-pheny1–1,2,3,6-tetrahydropyridine. Durg. Metab. Dispos. 13, 342–347.
Dinovo, E.G., Gottschalk, L.A., Noindi, B.R. and Geddes, P.D. (1976). GLC analysis of thioridazine, mesoridazine and their metabolites. J. Pharma. Sci. 65, 667–669.
Gorrod, J.W. and Jenner, P. (1975). The metabolism of tobacco alkaloids. In Essays in Toxicology, Ed. Hayes, Jr., W.J., Academic Press, New York, Vol. 16, pp 35.
Gorrod, J.W., Temple, D.J. and Beckett, A.H. (1975). The metabolism of N-ethyl-methylaniline by rabbit liver microsomes. The measurement of metabolites by gas-liquid chromatography. Xenobiotica 5, 435–464.
Hallstrom, G., Lindeke, B. and anderson, E (1981). Metabolism of N-(5- pyrrolidinopent-3-yny1)-succinimide (BL 14) in rat liver preparations. Characterization of four oxidative reactions. Xenobiotica. 11, 459–471.
Hibberd, A.R. and Gorrod, J.W. (1980). Nicotine Al T(51) iminium ion: a reactive intermediate in nicotine metabolism. In Biological Reactive Intermediates-II, Chemical Mechanisms and Biological Effects, Part B. Eds. Synder, R., Parke, D.V., Kocsis, J.J., Jollow, D.J., Gibson, G.G. and Witmer, C.M. Plenum Press, New York, pp 1121.
Ho, B. and Castagnoli, Jr., N. (1980). Trapping of metabolically generated electro-philic species with cyanide ion: metabolism of 1-benzylpyrrolidine. J. Med. Chem. 23, 133–139.
Joag, M., Schmidt-Peetz, M., Lampen, P., Trevor, A. and Castagnoli, N. (1988). Metabolic studies on phencyclidine: characterization of a phencyclidine iminium ion metabolite. Chem. Res. Toxicol. 1, 128–131.
Hucker, H.B., Gillette, J.R. and Brodie, B.B. (1960). Enzymic pathway for the formation of cotinine, a major metabolite of nicotine in rabbit liver. J. Pharmacol. Exptl. Ther. 129, 94–100.
Hucker, H.B., Stauffer, S.C. and Rhodes, R.E. (1972). Metabolism of a pharmaco-logically active pyrrolidine derivative (prolintane) by lactam formation. Experientia. 28, 430–431.
Jenner, P., Gorrod, J.W. and Beckett, A.H. (1973). Species variation in the metabolism of R-(+)- and S-(-)-nicotine by a-C- and N-oxidation in vitro. Xenobiotica. 3, 573–580.
Lowry, D., Rosenbrough, H.J., Farr, A.L. and Randall, R.J. (1951). Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193, 265–275.
McKennis, Jr, H., Turnbull, L.B. and Bowman, E.R. (1957). y-3(3-pyridy1)-y-methylaminobutyric acid as a urinary metabolite of nicotine. J. Am. Chem. Soc. 79, 6342.
McQuinn, R.L., Quarfoth, G.J., Johnson, J.D., Banitt, E.H., Pathre, S.V., Chang, S.F., Ober, R.E. and Conard, G.J. (1984). Biotransformation and elimination of 14C-flecanide acetate in humans. Durg. Metab. Dispos. 12, 414.
Millar, G.L. (1959). Protein determination for large numbers of samples. Anal. Chem. 31, 964.
Millar, A.L. and Larson, P.J. (1953). Observations on the metabolism of nicotine by tissue slices. J. Pharm. Exp. therap. 109, 2218–2222.
Murphy, P. (1973). Enzymatic oxidation of nicotine to nicotine Al 1(51 iminium ion, a newly discovered intermediate in the metabolism of nicotine. J. Biol. Chem. 248, 2796–2800.
Nakayama, H. (1988). Nicotine metabolism in mammals. Drug. Metab. Drug. Interac. 6, 95–122.
Nguyen, T., Gruenke, L.D. and Castagnoli, N. (1979). Metabolic oxidation of nicotine chemically reactive intermediates. J. Med. Chem. 22, 259–263.
Omura, T. and Sato, R. (1962). A new cytochrome in liver microsomes. J. Biol. Chem. 237, 1375–1376.
Paeme, G., Grimee, R. and Vercruysse, A. (1984). In vitro metabolism of procyclidine in the Rat. Erur. J. Metab. Pharmaco. 9, 311–313.
Pitts, J.E., Bruce, R.B. and Forehand, J.B. (1973). Identification of doxapram metabolites using high pressure ion exchange chromatography and mass spectroscopy. Xenobiotica. 3, 73–83.
Rekker, R.F. (1977). The hydrophobic fragmental constant: its derivation and application: a means of characterizing membrane systems. Pharmacochemistry Libray, Vol. 1. Elservir Scientific Publishing Co., Amsterdam.
Schenkman, J.B. and Cinti, D.L. (1975). Preparation of microsomes with calcium. Method in Enzymology 52, 83–89.
Singer, S.S., Lijinsky, V., Kratz, L.E., Castagnoli, Jr., N. and Rose, J.E. (1987). A comparison of in vivo and in vitro metabolites of the H1-antagonist N,Ndimethyl-N-2-pyridyl-N-(2-thienylmethyl)-1,2-ethane-diamine (methapyrilene) in the rat. Xenobiotica 17, 1279–1291.
Tham, R., Norlander, B., Hagermark, O. and Fransson, L. (1978). Gas chromatography of clemastine. A study of plasma kinetics and biological effect. Arzneim. Forsch. 28, 1017–1020.
Yoshihara, S. and Yoshimura, H. (1972). Metabolism of drugs-LXXVIII the formatin in vitro of oxoprolintane by rabbit liver. Biochem. Pharmacol. 21, 3205–3211.
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© 1991 Plenum Press, New York
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Gorrod, J.W., Whittlesea, C.M.C., Lam, S.P. (1991). Trapping of Reactive Intermediates by Incorporation of 14C-Sodium Cyanide during Microsomal Oxidation. In: Witmer, C.M., Snyder, R.R., Jollow, D.J., Kalf, G.F., Kocsis, J.J., Sipes, I.G. (eds) Biological Reactive Intermediates IV. Advances in Experimental Medicine and Biology, vol 283. Springer, Boston, MA. https://doi.org/10.1007/978-1-4684-5877-0_82
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