This pathway shows metabolism of nicotine in human liver including all the candidate genes which may be responsible. Nicotine is extensively metabolized to a number of metabolites in liver. Quantitatively, the most important metabolite of nicotine in most mammalian species is cotinine. In humans, about 70 to 80% of nicotine is converted to cotinine. This transformation involves two steps. The first is mediated by the cytochrome P450 system (mainly CYP2A6 and CYP2B6) to produce nicotine iminium ion. Both of these genes have polymorphisms that can effect this process, for more details see VIP gene information for CYP2A6 and CYP2B6. The second step is catalyzed by aldehyde oxidase (AOX). Nicotine N'-oxide (NNO) is another primary metabolite of nicotine, although only about 4-7% of nicotine absorbed by smokers is metabolized via this route. The conversion of nicotine to NNO involves a flavin-containing monooxygenase 3 (FMO3). It appears that NNO is not further metabolized to any significant extent, except by reduction back to nicotine, which may lead to recycling of nicotine in the body. Nicotine glucuronidation results in an N-quaternary glucuronide in humans. This reaction is catalyzed by uridine diphosphate-glucuronosyltransferase (UGT) enzyme(s) producing (S)-nicotine-N-¿-glucuronide (Nicotine-Gluc). Recent in vitro experiments suggest that UGT2B10 may be the primary enzyme in liver responsible for this conversion and that gene polymorphisms may influence this. About 3-5% of nicotine is converted to Nicotine-Gluc and excreted in urine in humans. Conversion of nicotine to nornicotine in humans has been demonstrated, and this process has been shown to be mediated by cytochrome P450 system in rabbits.
A number of cotinine metabolites have also been structurally characterized. Indeed, it appears that most of the reported urinary metabolites of nicotine are derived from cotinine. 3'-Hydroxycotinine (3HC) is the main nicotine metabolite detected in smokers' urine. It is also excreted as a glucuronide conjugate (3HC-Gluc). 3HC and 3HC-Gluc account for 40-60% of the nicotine dose in urine. As with NNO, cotinine N-oxide (CNO) can be reduced back to the parent amine in vivo as evidenced by a study in rabbits. Studies with CYP enzyme inhibitors in hamster and guinea pig liver microsomes show, that unlike NNO, CNO is formed by CYP enzymes. Norcotinine has been detected in smokers' urine (about 1% of total nicotine and metabolites). Two pathways for its formation are possible, demethylation of cotinine or oxidative metabolism of nornicotine. Animal and human studies have demonstrated the existence of both of these pathways.
There are additional important metabolites of nicotine that are not formed to any great extent endogenously as shown by experiments with nicotine patches as the drug delivery method, but are formed during the tobacco smoking process. The most well characterized as carcinogens so far are NNK (4-(methylnitrosamino)
1(3-pyridyl)-1-butanone) and NNAL (4-(methylnitrosamino) 1(3-pyridyl)-1-butanol). Although not depicted here these carcinogens are also metabolized by some of the same enzymes that metabolise nicotine including CYP2A6, UGT2B10, UGT1A4 and CYP2A13.
M. Whirl-Carrillo, E.M. McDonagh, J. M. Hebert, L. Gong, K. Sangkuhl, C.F. Thorn, R.B. Altman and T.E. Klein. "Pharmacogenomics Knowledge for Personalized Medicine" Clinical Pharmacology & Therapeutics (2012) 92(4): 414-417. Full text
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Entities in the Pathway
Relationships in the Pathway
|Arrow From||Arrow To||Controllers||PMID|
|3-hydroxycotinine||3-hydroxycotinine glucuronide||UGT1A4, UGT2B7||15470160|
|cotinine||3-hydroxycotinine||CYP2A13, CYP2A6||15528319, 16188955, 8627511|
|cotinine||cotinine glucuronide||UGT1A4, UGT1A9, UGT2B10, UGT2B7||12433823, 17576790|
|Nicotine iminium ion||cotinine||AOX1, AOX2P|
|nicotine||nicotine glucuronide||UGT1A4, UGT1A9, UGT2B10, UGT2B7||12433823, 17576790|
|nicotine||Nicotine iminium ion||CYP2A13, CYP2A6, CYP2B6||10350185, 10544257, 10999944, 11180041, 11207029, 15475735, 15528319, 15564629, 15592323, 15735609, 15940289, 16272956, 8937855|
|nicotine||nicotine N-oxide||FMO3||1446003, 3380084|
|3-hydroxycotinine glucuronide||3-hydroxycotinine glucuronide|
|5-hydroxycotinine glucuronide||5-hydroxycotinine glucuronide|
|cotinine glucuronide||cotinine glucuronide|
|cotinine N-oxide||cotinine N-oxide|
|nicotine glucuronide||nicotine glucuronide|
|nicotine N-oxide||nicotine N-oxide|
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|Pharmacogenetics of smoking cessation: role of nicotine target and metabolism genes. Human genetics. 2012. Gold Allison B, Lerman Caryn.|