Nicotine alkaloids metabolism

Among the alkaloids are some well-known (and dangerous) compounds. Nicotine is an agent in tobacco that has been described as one of the most toxic of all poisons and (it) acts with great rapidity. 13 In 1988, the U.S. Surgeon General declared nicotine to be an addictive substance. Nicotine is metabolized to cotinine and iran.v-3 -hydroxycotinine,... 

PMT and H6H, which catalyze the first and last steps, respectively, in the biosynthesis of the tropane alkaloid scopolamine (Scheme 3), were localized to the pericycle in the roots of A. belladonna and Hyoscyamus muticus (Fig. 2A) 132,145). PMT also catalyzes the first step in nicotine biosynthesis (Scheme 3) and has been localized to the endodermis, outer cortex, and xylem in N. sylvestris (244,245). In contrast, TR-I, an intermediate enzyme in the tropane alkaloid pathway, resides in the endodermis and nearby cortical cells (Fig. 2A) (135) thus, intermediates of tropane alkaloid metabolism must also be transportai between cell types. The biosynthesis and storage of acridone alkaloids were also associated with endodermis in Ruta graveolens (246). 

Experiments performed on the nicotinic acid-ricinine relationship in sterile cultures of R, communis established clearly that (1) the relationship exists, and (2) the metabolism of ricinine can be spared by the presence of higher concentrations of nicotinic acid than normally found in the tissue (Waller and Nakazawa, 1963). This sparing action of nicotinic acid on ricinine utilization suggests a vitamin-alkaloid metabolic relationship not previously found in a plant system. 

Furthermore, SAM not only plays a pivotal role in PA and ethylene biosynthesis, but also in the formation of putrescine-derived alkaloids. Thus, SAM acts as a methyl donor in the conversion of putrescine into A-methylputresdne, an intermediate in the biosynthesis of nicotine (Mizusaki et al., 197 lb). Therefore, it would be interesting to explore the auxin-ethylene-PAs interaction on PA conjugates and putrescine-derived alkaloids metabolism in the above-mentioned tobacco callus tissue system. Indeed, it has been reported that inhibition of SAM decarboxylase by MGBG resulted in an increase of nicotine production in tobacco root cell suspension cultures (Blume, 1985). Unfortunately, nothing about PA conjugates was indicated in this report. 

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). 

Nicotine is well absorbed from the mucous membranes in the oral cavity, gastrointestinal tract, and respiratory system. If tobacco smoke is held in the mouth for 2 seconds, 66 to 77% of the nicotine in the smoke will be absorbed across the oral mucosa. If tobacco smoke is inhaled, approximately 90 to 98% of the nicotine will be absorbed. Nicotine is distributed throughout the body, readily crossing the blood-brain and placental barriers. The liver, kidney, and lung metabolize approximately 80 to 90% of the alkaloid. The kidney rapidly eliminates nicotine and its metabolites. 

Nicotine is rapidly excreted by three insect species that normally feed on Nicotiana tabacum (10,11). Manduca sexta. Trichoplusia ni, and Heliothis virescens eliminate the unchanged alkaloid after Ingestion, and no evidence was obtained to indicate that nicotine was subjected to any metabolic transformations. 

Nicotine (I) is metabolized to contlnlne (II) by various insects. Including species adapted to feed on alkaloid-containing leaves and those that are not. Contlnlne, which is virtually nontoxic to Insects, is the primary nicotine metabolite produced by some coleopterous and orthopterous species that feed on tobacco other minor metabolites are produced as well (11). Two species of cockroaches and the housefly, Musca domestlca, also convert nicotine to contlnlne, although these insects do not normally feed on nicotine-fortified plants (11). 

The tobacco alkaloid nicotine (96) (B-67MI10702) is insecticidal by virtue of its action on the acetylcholine receptor. It was used widely as an aphicide, especially as a fumigant. Another natural product thought to act on the same receptor is the 1,2-dithiolane nereistoxin (97) (B-72MI10703), isolated from the marine annelid Lumbriconereis heteropoda. The active form has been shown to be the ring opened dithiol (98), and the protected form of it, cartap (99), is sold as a rice insecticide. The 1,2,3-trithiane thiocyclam (100) (72SAP7007824) is also active, presumably because of metabolic conversion to (98). 

Gonod. J.W. and J. Wahren Nicotine and Related Alkaloids. Adsorption, Distribution, Metabolism and Excretion, Chapman Hall. New York, NY, 1993. 

I), other important alkaloids are used as amine reagents for Mannich synthesis. Thus, demethylatcd nicotine affords aminomethylation of hydrogen cyanide (460), employed in studies of the metabolic oxidation of nicotine, and anabasinc gives, by reaction with acrylamide, the readily polymerizable monomeric species 461, the polymeric derivative of which is. 50 times less toxic than the original anabasinc. ... 

Acetylcholine receptors (AChRs) are of two types muscarinic (mAChR) and nicotinic (nAChR) based on the agonist activities of the natural alkaloids, muscarine and nicotine, respectively. These receptors are functionally different. The muscarinic type being G-protein coupled receptors mediate a slow metabolic response via second messenger cascades, while the nicotinic type are ligand-gated ion channels, which mediate a fast synaptic transmission of the neurotransmitter. Skeletal muscles are enriched with nAChRs and are devoid of mAChRs. 

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