Nicotine Metabolism (Homo sapiens)

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Liver cellCotinine N-oxideCotinineCYP2A6CYP2B6Nicotine iminium ionNornicotine3'-Hydroxycotinine3'-Hydroxycotinine glucuronide3'-HydroxycotinineNicotine-GlucCotinine N-oxideUGT1A4FMO3UGT1A9Nicotine-GlucNornicotineNicotine-N-oxide5'-HydroxycotinineCYP2A6CotinineglucuronideCotinineNornicotineNornicotineNicotine-N-oxideCotinineglucuronideNicotineNicotine5'-Hydroxycotinine3'-Hydroxycotinine glucuronideAOX1CYP2A6


Description

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.

Nicotine pharmacokinetics, Nicotine at Wikipedia

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Bibliography

  1. Hukkanen J, Jacob P 3rd, Benowitz NL; ''Metabolism and disposition kinetics of nicotine.''; Pharmacol Rev, 2005 PubMed Europe PMC Scholia
  2. Benowitz NL, Hukkanen J, Jacob P 3rd; ''Nicotine chemistry, metabolism, kinetics and biomarkers.''; Handb Exp Pharmacol, 2009 PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
106147view12:04, 16 August 2019MaintBotHMDB identifier normalization
99039view08:54, 26 October 2018DeSlModified description
96391view07:15, 12 March 2018Asios OliaModified description
96390view07:13, 12 March 2018Asios OliaModified description
96389view07:07, 12 March 2018Asios OliaModified description
96388view07:06, 12 March 2018Asios OliaModified description
96387view07:05, 12 March 2018Asios OliaModified description
96386view07:05, 12 March 2018Asios OliaModified description
92822view19:45, 8 July 2017AlexanderPicoOntology Term : 'drug pathway' added !
92778view11:30, 4 July 2017DeSlOntology Term : 'xenobiotic metabolic pathway' added !
90593view07:00, 28 November 2016EgonwModified description
90565view09:49, 25 November 2016EgonwAdded two lit references.
89933view13:44, 6 October 2016EgonwModified description
70113view19:10, 12 July 2013MaintBotupdated to 2013 schema
70026view01:53, 12 July 2013AlexanderPicoModified title
67507view11:18, 26 June 2013DdiglesOntology Term : 'nicotine pathway' added !
56442view21:37, 7 January 2013EgonwAdded a missing HMDB data source value.
46348view12:55, 19 January 2012EgonwPeriodical save, work in progress
45359view20:45, 7 October 2011KhanspersOntology Term : 'hepatocyte' added !
41180view23:42, 1 March 2011MaintBotRemoved redundant pathway information and comments
38479view18:19, 17 September 2010AlexanderPicoModified description
38342view20:45, 1 September 2010KhanspersChanged name
38341view19:16, 1 September 2010KhanspersModified description
38329view18:47, 1 September 2010KhanspersChanged DataNode type and arrows
38300view21:16, 30 August 2010KhanspersChanged arrows to catalysis
38299view21:14, 30 August 2010KhanspersModified description
38298view21:13, 30 August 2010KhanspersModified description
38297view21:12, 30 August 2010KhanspersModified description
38218view20:52, 27 August 2010KhanspersModified categories
38217view20:50, 27 August 2010KhanspersModified description
38216view20:49, 27 August 2010KhanspersChanged name
38215view20:48, 27 August 2010KhanspersNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
3'-Hydroxycotinine glucuronideMetaboliteHMDB01204
3'-Hydroxycotinine glucuronideMetaboliteHMDB01204 (HMDB)
3'-HydroxycotinineMetaboliteHMDB01390 (HMDB)
5'-HydroxycotinineMetaboliteHMDB01427 (HMDB)
AOX1GeneProduct316 (Entrez Gene)
CYP2A6GeneProduct1548 (Entrez Gene)
CYP2B6GeneProduct1555 (Entrez Gene)
Cotinine N-oxideMetaboliteHMDB01411 (HMDB)
CotinineMetaboliteHMDB01046 (HMDB)
CotinineglucuronideMetaboliteHMDB01013 (HMDB)
FMO3GeneProduct2328 (Entrez Gene)
Nicotine iminium ionMetaboliteHMDB01010 (HMDB)
Nicotine-GlucMetaboliteHMDB01272 (HMDB)
Nicotine-N-oxideMetaboliteHMDB01497 (HMDB)
NicotineMetaboliteHMDB01934 (HMDB)
NornicotineMetaboliteHMDB01126 (HMDB)
UGT1A4GeneProduct54657 (Entrez Gene)
UGT1A9GeneProduct54600 (Entrez Gene)

Annotated Interactions

No annotated interactions

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