Nicotine-A -oxides

The major human urinary metabolites of nicotine are cotinine, nicotine A -oxide, and fra s-3 -hydroxycotinine (113). CYP2A6 appears to be the major enzyme responsible for formation of an iminium ion that is the first step in the C-5 oxidation of nicotine to cotinine and also the subsequent... 

Pyridine, 3-(1-methyl-2-pyrrolidinyl)-, 1-oxide, (S)- nicotine A/-oxide ... 

The oxidation of nicotine with hydrogen peroxide yields, besides nicotinic acid and nicotine-A -oxide (345), an oxynicotine (315), which is also produced when an aqueous solution of nicotine is oxidized by air under the influence of sunlight (346) or ultraviolet radiation (347). Formula (CXLII) for nicotine enabled Pinner (316) and Wolffenstein (317) to show that oxynicotine is not a primary product of oxidation, but a condensation product consisting of two substances, nicotine and nicotol. 

I. 2,3 -PyridylpyrroIidines and their dalvatives, e.g., nicotine, nomicotine, myosmine, nicotyrine, cotinine, A -acylnomicotines, nicotine-A -oxides... 

Pyridine A Oxides. Analgesic and antiinflammatory dmgs niflumic acid [4394-00-7] (68) and pranoprofen [52549-17-4] (69) are manufactured from nicotinic acid N-oxide [2398-81 -4]. The antiulcer dmg omeprazole (66) is produced from 2,3,5-trimethylpyridine N-oxide [74409-42-0]. Zinc pyrithione, the zinc salt of pyrithione (45), is a fungicide derived from 2-chloropyridine N-oxide (45). 

In two publications [36, 37] and a subsequent review [38], a closely related alternative procedure for conversion of pyridine-N-oxides into cyanopyridines was reported in 1983. This used a combination of the mild Lewis acid Me2NCOCl and trimethylsilyl cyanide 18 for the cyanation of pyridine N-oxides such as 860, affording, in CH2CI2, via 932 and 933, 2-cyanopyridine 862 in 94% yield and apparently no 4-cyanopyridine 864 [36-38] (Scheme 7.13). With 3-substituted pyridine N-oxides such as methyl nicotinate N-oxide a mixture of 40% methyl 2-cyanonico-tinate and 60% methyl 6-cyanonicotinate is obtained. 

Ensign JC, SC Rittenberg (1964) The pathway of nicotinic acid oxidation by a Bacillus species. J Biol Chem 239 2285-2291. 

Hibberd and Gorrod incubated nicotine-A-l -(5 )-iminium (152) with hepatic homogenates prepared from mouse, rat, hamster, rabbit, guinea pig, and human fetal liver to demonstrate the involvement of such reactive chemical intermediates in the oxidation of nicotine to cotinine (151) 221). The iminium ion (152) was converted to (151) more rapidly than nicotine, thus confirming the intermediacy of the ion between nicotine and cotinine. A series of inconclusive... 

Quantitative aspects of the pattern of nicotine metabolism have been elucidated fairly well in people (Fig. 4). Approximately 90% of a systemic dose of nicotine can be accounted for as nicotine and metabolites in urine (Benowitz et al. 1994). Based on studies with simultaneous infusion of labeled nicotine and cotinine, it has been determined that 70-80% of nicotine is converted to cotinine (Benowitz and Jacob 1994). About 4-7% of nicotine is excreted as nicotine N -oxide and 3-5% as nicotine glucuronide (Benowitz et al. 1994 Byrd et al. 1992). Cotinine is excreted unchanged in urine to a small degree (10-15% of the nicotine and metabolites in urine). The remainder is converted to metabolites, primarily fra i -3 -hydroxycotinine (33 0%), cotinine glucuronide (12-17%), and trans-3 -hydroxycotinine glucuronide (7-9%). 

Renal clearance of cotinine is much less than the glomerular filtration rate (Benowitz et al. 2008b). Since cotinine is not appreciably protein bound, this indicates extensive tnbnlar reabsorption. Renal clearance of cotinine can be enhanced by np to 50% with extreme urinary acidification. Cotinine excretion is less influenced by urinary pH than nicotine becanse it is less basic and, therefore, is primarily in the unionized form within the physiological pH range. As is the case for nicotine, the rate of excretion of cotinine is influenced by urinary flow rate. Renal excretion of cotinine is a minor route of elimination, averaging about 12% of total clearance. In contrast, 100% of nicotine Ai -oxide and 63% of 3 -hydroxycotinine are excreted unchanged in the urine (Benowitz and Jacob 2001 Park et al. 1993). 

Messina ES, Tyndale RF, Sellers EM (1997) A major role for CYP2A6 in nicotine C-oxidation by human liver microsomes. J Pharmacol Exp Ther 282(3) 1608-1614 Meunier V, Bourrie M, Julian B, Marti E, GuUlou F, Berger Y, Fabre G (2000) Expression and induction of CYPl A1/1A2, CYP2A6 and CYP3 A4 in primary cultures of human hepatocytes a 10-year follow-up. Xenobiotica 30(6) 589-607... 

Mouse CYP2A5 is a comparable isoform to human CYP2A6 (Raunio et al. 1988), because these isozymes are responsible for the majority of nicotine s C-oxidation (Raunio et al. 2008), cotinine s subsequent oxidation to 3 -hydroxycotinine (Sin and Tyndale 2007), and coumarin 7-hydroxylation (Kaipainen et al. 1984). Taken together, these findings suggest that mice may be a cost-effective animal model of human CYP2A6-mediated nicotine C-oxidation. 

Munafo M, Clark T, Johnstone E, Murphy M, Walton R (2004) The genetic basis for smoking behavior a systematic review and meta-analysis. Nicotine Tob Res 6 583-597 Murphy SE, Raulinaitis V, Brown KM (2005) Nicotine 5 -oxidation and methyl oxidation by P450 2A enzymes. Drug Metab Dispos 33 1166-1173... 

C. L. Crowley-Weber, K. Dvorakova, C. Crowley, H. Bernstein, C. Bernstein, H. Garewal and C. M. Payne, Nicotine increases oxidative stress, activates NF-kappaB and GRP78, induces apoptosis and sensitizes cells to genotoxic/xenobiotic stresses by a multiple stress inducer, deoxy-cholate relevance to colon carcinogenesis, Chem. Biol. Interact., 2003, 145(1), 53. 

Asymmetric IR or Raman stretching vibration of an RnO unit Symmetric IR or Raman stretching vibration of an RuO unit Stretching vibration of an Ru=0 unit Nicotinate dianion N -methyhnorphofine-A-oxide Not observed... 

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. 

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