ChemBridge Corporation Screening Compounds Sign up for PNAS Online eTocs
Link: Info for AuthorsLink: Editorial BoardLink: AboutLink: SubscribeLink: AdvertiseLink: ContactLink: Sitemap Link: PNAS Home
Proceedings of the National Academy of Sciences
Link: Current Issue "" Link: Archives "" Link: Online Submission ""  Link: Advanced Search

Published online on October 24, 2000, 10.1073/pnas.220207697
PNAS | November 7, 2000 | vol. 97 | no. 23 | 12493-12497


This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via ISI Web of Science (32)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hecht, S. S.
Right arrow Articles by Murphy, S. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hecht, S. S.
Right arrow Articles by Murphy, S. E.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg  
What's this?

 Previous Article  | Table of Contents |  Next Article 

Biochemistry
 2'-Hydroxylation of nicotine by cytochrome P450 2A6 and human liver microsomes: Formation of a lung carcinogen precursor

Stephen S. Hecht*, J. Bradley Hochalter, Peter W. Villalta, and Sharon E. Murphy

University of Minnesota Cancer Center, Minneapolis, MN 55455

Edited by Allan H. Conney, Rutgers, The State University of New Jersey, Piscataway, NJ, and approved September 1, 2000 (received for review May 8, 2000)

Smokers or people undergoing nicotine replacement therapy excrete approximately 10% of the nicotine dose as 4-oxo-4-(3-pyridyl)butanoic acid (keto acid) and 4-hydroxy-4-(3-pyridyl)butanoic acid (hydroxy acid). Previously, these acids were thought to arise by secondary metabolism of the major nicotine metabolite cotinine, but our data did not support this mechanism. Therefore, we hypothesized that nicotine is metabolized by 2'-hydroxylation, which would ultimately yield keto acid and hydroxy acid as urinary metabolites. This pathway had not been established previously in mammalian systems and is potentially significant because the product of nicotine 2'-hydroxylation, 4-(methylamino)-1-(3-pyridyl)-1-butanone (aminoketone), can be converted to the potent tobacco-specific lung carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Incubation of nicotine with cytochrome P450 2A6 and cofactors did indeed produce aminoketone, which was identified as its N-benzoyl derivative by GC-MS. The rate was 11% of that of cotinine production. Incubation of human liver microsomes with nicotine gave keto acid by using aminoketone as an intermediate; keto acid was not formed from cotinine. In 10 human liver samples, rates of formation of keto acid were 5.7% of those of cotinine and production of these metabolites correlated. These results provide definitive evidence for mammalian 2'-hydroxylation of nicotine and elucidate a pathway by which endogenous formation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone could occur in humans.

* To whom reprint requests should be addressed at: University of Minnesota Cancer Center, Box 806 Mayo, 420 Delaware Street SE, Minneapolis, MN 55455. E-mail: hecht002{at}tc.umn.edu.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg    What's this?


This article has been cited by other articles in HighWire Press-hosted journals:


Home page
 Appl. Environ. Microbiol.Home page
H. Tang, S. Wang, L. Ma, X. Meng, Z. Deng, D. Zhang, C. Ma, and P. Xu
A Novel Gene, Encoding 6-Hydroxy-3-Succinoylpyridine Hydroxylase, Involved in Nicotine Degradation by Pseudomonas putida Strain S16
Appl. Envir. Microbiol., March 1, 2008; 74(5): 1567 - 1574.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
X. Zhang, J. D'Agostino, H. Wu, Q.-Y. Zhang, L. von Weymarn, S. E. Murphy, and X. Ding
CYP2A13: Variable Expression and Role in Human Lung Microsomal Metabolic Activation of the Tobacco-Specific Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone
J. Pharmacol. Exp. Ther., November 1, 2007; 323(2): 570 - 578.
[Abstract] [Full Text] [PDF]

Home page
 MicrobiologyHome page
S. N. Wang, Z. Liu, H. Z. Tang, J. Meng, and P. Xu
Characterization of environmentally friendly nicotine degradation by Pseudomonas putida biotype A strain S16
Microbiology, May 1, 2007; 153(5): 1556 - 1565.
[Abstract] [Full Text] [PDF]

Home page
 J Health PsycholHome page
K. H. Ginzel, G. S. Maritz, D. F. Marks, M. Neuberger, Jim. R. Pauly, J. R. Polito, R. Schulte-Hermann, and T. A. Slotkin
Critical Review: Nicotine for the Fetus, the Infant and the Adolescent?
J Health Psychol, March 1, 2007; 12(2): 215 - 224.
[Abstract] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
L. B. von Weymarn, K. M. Brown, and S. E. Murphy
Inactivation of CYP2A6 and CYP2A13 during Nicotine Metabolism
J. Pharmacol. Exp. Ther., January 1, 2006; 316(1): 295 - 303.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Z.-L. Wu, L. M. Podust, and F. P. Guengerich
Expansion of Substrate Specificity of Cytochrome P450 2A6 by Random and Site-directed Mutagenesis
J. Biol. Chem., December 9, 2005; 280(49): 41090 - 41100.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
K. E. Dicke, S. M. Skrlin, and S. E. Murphy
NICOTINE AND 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-BUTANONE METABOLISM BY CYTOCHROME P450 2B6
Drug Metab. Dispos., December 1, 2005; 33(12): 1760 - 1764.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
S. E. Murphy, V. Raulinaitis, and K. M. Brown
NICOTINE 5'-OXIDATION AND METHYL OXIDATION BY P450 2A ENZYMES
Drug Metab. Dispos., August 1, 2005; 33(8): 1166 - 1173.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
W. K.K. Wu, H. P.S. Wong, S. W. Luo, K. Chan, F. Y. Huang, M. K.C. Hui, E. K.Y. Lam, V. Y. Shin, Y. N. Ye, Y. H. Yang, et al.
4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone from Cigarette Smoke Stimulates Colon Cancer Growth via {beta}-Adrenoceptors
Cancer Res., June 15, 2005; 65(12): 5272 - 5277.
[Abstract] [Full Text] [PDF]

Home page
 Pharmacol. Rev.Home page
J. Hukkanen, P. Jacob III, and N. L. Benowitz
Metabolism and Disposition Kinetics of Nicotine
Pharmacol. Rev., March 1, 2005; 57(1): 79 - 115.
[Abstract] [Full Text] [PDF]

Home page
 J. Dent. Res.Home page
R.D.C. Barley, S. Pollock, M.C. Shallow, E. Peters, and E.W.N. Lam
Tobacco-related-compound-induced Nitrosative Stress Injury in the Hamster Cheek Pouch
J. Dent. Res., December 1, 2004; 83(12): 903 - 908.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
S. E. Murphy, C. A. Link, J. Jensen, C. Le, S. S. Puumala, S. S. Hecht, S. G. Carmella, L. Losey, and D. K. Hatsukami
A Comparison of Urinary Biomarkers of Tobacco and Carcinogen Exposure in Smokers
Cancer Epidemiol. Biomarkers Prev., October 1, 2004; 13(10): 1617 - 1623.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
G. E. Kuehl and S. E. Murphy
N-GLUCURONIDATION OF NICOTINE AND COTININE BY HUMAN LIVER MICROSOMES AND HETEROLOGOUSLY EXPRESSED UDP-GLUCURONOSYLTRANSFERASES
Drug Metab. Dispos., November 1, 2003; 31(11): 1361 - 1368.
[Abstract] [Full Text] [PDF]

Home page
 Hum Exp ToxicolHome page
D F. Lewis, M G Bird, and M N Jacobs
Human carcinogens: an evaluation study via the COMPACT and HazardExpert procedures
Human and Experimental Toxicology, March 1, 2002; 21(3): 115 - 122.
[Abstract] [PDF]

Home page
 J. Biol. Chem.Home page
E. M. Leslie, K.-i. Ito, P. Upadhyaya, S. S. Hecht, R. G. Deeley, and S. P. C. Cole
Transport of the beta -O-Glucuronide Conjugate of the Tobacco-specific Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) by the Multidrug Resistance Protein 1 (MRP1). REQUIREMENT FOR GLUTATHIONE OR A NON-SULFUR-CONTAINING ANALOG
J. Biol. Chem., July 20, 2001; 276(30): 27846 - 27854.
[Abstract] [Full Text] [PDF]