Abstract
Nicotine is the major addictive agent in tobacco smoke, and it is metabolized extensively by oxidation and glucuronide conjugation. The contributions of ethnicity and UGT2B10 haplotype on variation in nicotine metabolism were investigated. Nicotine metabolism was evaluated in two populations of smokers. In one population of African American and European American smokers (n = 93), nicotine and its metabolites were analyzed in plasma and 24-h urine over 3 days while participants were abstinent and at steady state on the nicotine patch. In a second study of smokers (n = 84), the relationship of a UGT2B10 haplotype linked with D67Y to nicotine and cotinine glucuronidation levels was determined. We observed that both African American ethnicity and the UGT2B10 D67Y allele were associated with a low glucuronidation phenotype. African Americans excreted less nicotine and cotinine as their glucuronide conjugates compared with European Americans; percentage of nicotine glucuronidation, 18.1 versus 29.3 (p < 0.002) and percentage of cotinine glucuronidation, 41.4 versus 61.7 (p < 0.0001). In smokers with a UGT2B10 Tyr67 allele, glucuronide conjugation of nicotine and cotinine was decreased by 20% compared with smokers without this allele. Two key outcomes are reported here. First, the observation that African Americans have lower nicotine and cotinine glucuronidation was confirmed in a population of abstinent smokers on the nicotine patch. Second, we provide the first convincing evidence that UGT2B10 is a key catalyst of these glucuronidation pathways in vivo.
Footnotes
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This work was supported in part by the National Institutes of Health National Institute on Drug Abuse [Grants DA13333, 1F30-DA020968]; and the National Institutes of Health National Institute of General Medical Sciences [Grant MSTP T32-GM08244] (Medical Scientist Training Program).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.159855
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ABBREVIATIONS:
- cpd
- cigarettes per day
- P450
- cytochrome P450
- UGT
- UDP glucuronosyltransferase
- TRIP
- Tobacco Reduction Intervention Program
- GC/MS
- gas chromatography/mass spectrometry
- RFLP
- restriction fragment length polymorphism
- SNP
- single-nucleotide polymorphism
- HPLC
- high-performance liquid chromatography
- UDPGA
- UDP-glucuronic acid.
- Received August 3, 2009.
- Accepted September 21, 2009.
- © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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