Nicotine metabolites

Dwoskin, L.P., Leibee, L.L., Jewell, A.L., Fang, Z., and Crooks, P.A., Inhibition of [3H]dopamine uptake into rat striatal slices by quaternary V-methylated nicotine metabolites, Life Sci., 50, PL-223, 1992. 

Dempsey D, Jacob P, 3rd, Benowitz NL (2002) Accelerated metabolism of nicotine and cotinine in pregnant smokers. J Pharmacol Exp Ther 301(2) 594-598 Dempsey D, Tutka P, Jacob P, 3rd, Allen F, Schoedel K, Tyndale RF, Benowitz NL (2004) Nicotine metabolite ratio as an index of cytochrome P450 2A6 metabolic activity. Clin Pharmacol Ther 76 64-72... 

Kandel DB, Hu MC, Schaffran C, Udry JR, Benowitz NL (2007) Urine nicotine metabolites and smoking behavior in a multiracial/multiethnic national sample of young adults. Am J Epidemiol... 

Lerman C, Tyndale R, Patterson F, Wileyto EP, Shields PG, Pinto A, Benowitz N (2006) Nicotine metabolite ratio predicts efiScacy of transdermal nicotine for smoking cessation, Clin Pharmacol Ther79(6) 600-608... 

A. Crooks. Nornicotine, a nicotine metabolite and tobacco alkaloid desensitization of nicotinic receptor-stimulated dopamine release from rat striatum. Eur J Pharmacol 2001 428(1) 69-79. 

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). 

Nicotine forms a number of metabolites in the body, mainly in the liver. Approximate 75% of nicotine is oxidized to cotinine, which is the primary nicotine metabolite. Cotinine can be measured in the blood, urine, and saliva and this is used as a measure of nicotine exposure in tobacco users and in those exposed to secondhand smoke. The oxidation of nicotine also produces nicotinic acid. Nicotinic acid is vitamin B3 and has the common name niacin. Niacin deficiency results in a disease called pellagra, which is found in certain malnourished populations. Pellagras symptoms include dermatitis, diarrhea, sensitivity to light, and dementia. 

Molecular imprinting has been used to devise a chemosensor for L-nicotine (Table 6) [178]. For that, poly(methacrylic acid) (PMA) beads, imprinted with the L-nicotine template in chloroform, were incorporated in a film of the conjugated polymer, OCiC10-PPV. EIS has then been utilized for the L-nicotine determination in the 1-10 nM concentration range. This MIP chemosensor showed predominant affinity towards L-nicotine over a structurally related L-nicotine metabolite, L-cotinine. Similarly, the polydopamine-imprinted film prepared by electropolymerization in the phosphate buffer (pH = 7.4) has been used to devise a chemosensor for L-nicotine with LOD of 0.5 pM (Table 6) [106]. This LOD is still much higher than that reported for other L-nicotine determination methods based on MIPs, such as SPE combined with differential pulsed elution, which was 6 nM [31]. 

Synthesis of pyrrolidin-2-ones by cyclization through the generally disfavored 5-endo-trig mode has been reported [95JCS(P1)1115]. Treatment of the disulfanyl acetal 133 under reductive conditions furnished continine 134, a nicotine metabolite in high yield. Reaction of the corresponding dichloro or monochloro compound gave none or very small amounts of the cyclized compounds. 

Synthesis of (S)-6-hydroxymethylcotinine for use in radioimmunoassay analysis of nicotine metabolites was achieved by reacting (S)-cotinine with a carbon-centered radical derived from methanol <95JCR(S)246>. 

The 13C n.m.r. spectra of nicotine metabolites have been measured and discussed.39 The stereoselectivity of the iodomethylation of nicotine and seven analogues has been studied with the aid of 13C n.m.r. spectroscopy.40 Nicotine yields 2-methylnicotine as the major product when treated with methyl-lithium or methyl radicals, accompanied, as reported earlier, by 4- and 6-methylnicotine. Nicotine tV-oxide and methylmagnesium bromide afford 2- and 6-methyl-nicotines.41 Anabaseine (26), a well-known minor alkaloid of tobacco, has been identified as a poison-gland product in ants of the genus Aphaenogaster, which use it as an attractant.42... 

Olincy A, Young DA, Freedman R. 1997. Increased levels of the nicotine metabolite cotinine in schizophrenic smokers compared to other smokers. Biol Psychiatry 42 1-5. 

Myosmine (3[2-pyrrolidinyl]pyridine) and nicotine (3[l-methyl-2-pyrrolidinyl]pyridine) (Section 1, Appendix) and a number of related bioactive alkaloids occur in Nkotiana tabacum (tobacco) (Solanaceae) and variously in other Solanaceae such as Duboisia species. Nicotine and the related tobacco compounds nicotyrine and (—)-nornicotine are agonists (neurotransmitter mimics ) of the so-called (nicotine binding) nACh-R involved in neurotransmission and in neuromuscular transmission for skeletal muscle. The extraordinary addictiveness of nicotine derives from nACh-R agonists causing dopamine release and activating the mesolimbic dopamine system yielding reward effects. The antidepressant (—)-cotinine is the major nicotine metabolite in humans and a nicotinic agonist. 

Yes. In situations where drugs are known to be present in the environment, it is easy to demonstrate that passive exposure can produce positive hair analysis results. In a study by Haley and Hoffmaim of the nicotine and cotinine concentrations in the hair of smokers and nonsmokers, there appeared to be a higher average of nicotine in the unwashed hair of smokers (average 8.75 ng/mg). However, nonsmokers also had an appreciable level of nicotine (average 2.42 ng/mg) which overlapped that of smokers. In contrast, cotinine (the nicotine metabolite) does appear to be a marker of tobacco use in this population. More recently, Kintz and co-workers and Kintz proposed a cutoff level of 2 ng of nicotine/mg of hair to ehminate nonsmoking individuals. Even at this level, some nonsmokers would be positive. 

SCHEME 11.31 O-GlLicLironides (ethers) can form from phenols such as morphine (3-phenol), p-hydroxyphenobarbital (Scheme 11.1), p-hydroxyphenytoin (Figure 2.8), and alcohols such as morphine (6-hydroxyl). N-Glucuronides can be formed from aliphatic amines such as amitriptyline, or aromatic amines such as the nicotine metabolite cotinine. 

COtinine [inn] is an alkaloid from leaf tobacco (Nicotiana tabacum) and is also detected in Duboisia hopwoodii (Solanaceae). It is a nicotine metabolite, used as a biomarker for exposure to cigarette smoke. It shows ANTIDEPRESSANT and other behavioural effects in animals, cothromboplastin factorVII. 

Two examples of unusually large deuterium isotope effects in biological systems have been observed. The oxidative O-demethylation of trideu-teromethoxy anisole showed an isotope effect of —10 in vitro, 3 and the oxidation in vivo of cotinine, a nicotine metabolite, to 3-hydroxycotinine... 

Cotinine (NIH 10498) LecTec Pyrrolidinyl pyridine (nicotine metabolite) Nicotinic partial agonist... 

The untoward biological properties of nicotine and nicotine metabolites are controversial. Extensive epidemiological studies have supported a role of smoking in several types of cancer. However, although nicotine is a prominent component of cigarette smoke, there are thousands of other chemicals present in tobacco smoke, including most classes of known chemical carcinogens (Hecht and... 

In this chapter, nicotine or nicotine metabolites shall all be assumed to have the (5) stereochemistry at the benzylic center. 

Additionally it should be remembered that nicotine metabolites still retain a pyridyl moiety and this functional group can release nicotinamide from NADPH and generate an analogue of the coenzyme via a glycohydrolase. As these analogues may not be able to participate in the normal oxido/reduction reactions of intermediary metabolism certain pathways may be inhibited leading to accumulation of substrates e.g. glucose-6-phosphate and diminution of availability of products e.g. ribose, and thereby affect purine, pyrimidine and nucleic acid biosynthesis. 

Sporadic reports of effects of other nicotine metabolites on biological systems have appeared in the literature but these seem unlikely to produce major pharmacological or toxicological effects when metabolically derived from nicotine, due to the low levels formed. 

Cotlnlne, I-Methyl-5-(3-pyridinyli-2-pyrrolidin-one N-methyl-2-(3-pyridyl)-5-pyrrolidone. C.tH.2N20 mol wt 176.21. C 68.16%, H 6.86%, N 15.90%, O 9.08%. Nicotine metabolite first described by Pinner, Arch. Pharm. 231, 378 (1893). Isolated from autoxidized nicotine, nicotine treated with hydrogen peroxide, from nicotine irradiated with ultraviolet light Frankenburg, Vaitekunas, J. Am. 

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