Skip to main content
construction release_alert
Scholars@Duke will be undergoing maintenance April 11-15. Some features may be unavailable during this time.
cancel

Nicotine oxidation by genetic variants of CYP2B6 and in human brain microsomes.

Publication ,  Journal Article
Bloom, AJ; Wang, P-F; Kharasch, ED
Published in: Pharmacol Res Perspect
April 2019

Common variation in the CYP2B6 gene, encoding the cytochrome P450 2B6 enzyme, is associated with substrate-specific altered clearance of multiple drugs. CYP2B6 is a minor contributor to hepatic nicotine metabolism, but the enzyme has been proposed as relevant to nicotine-related behaviors because of reported CYP2B6 mRNA expression in human brain tissue. Therefore, we hypothesized that CYP2B6 variants would be associated with altered nicotine oxidation, and that nicotine metabolism by CYP2B6 would be detected in human brain microsomes. We generated recombinant enzymes in insect cells corresponding to nine common CYP2B6 haplotypes and demonstrate genetically determined differences in nicotine oxidation to nicotine iminium ion and nornicotine for both (S) and (R)-nicotine. Notably, the CYP2B6.6 and CYP2B6.9 variants demonstrated lower intrinsic clearance relative to the reference enzyme, CYP2B6.1. In the presence of human brain microsomes, along with nicotine-N-oxidation, we also detect nicotine oxidation to nicotine iminium ion. However, unlike N-oxidation, this activity is NADPH independent, does not follow Michaelis-Menten kinetics, and is not inhibited by NADP or carbon monoxide. Furthermore, metabolism of common CYP2B6 probe substrates, methadone and ketamine, is not detected in the presence of brain microsomes. We conclude that CYP2B6 metabolizes nicotine stereoselectively and common CYP2B6 variants differ in nicotine metabolism activity, but did not find evidence of CYP2B6 activity in human brain.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Pharmacol Res Perspect

DOI

EISSN

2052-1707

Publication Date

April 2019

Volume

7

Issue

2

Start / End Page

e00468

Location

United States

Related Subject Headings

  • Tobacco Use Disorder
  • Stereoisomerism
  • Recombinant Proteins
  • Polymorphism, Single Nucleotide
  • Oxidation-Reduction
  • Nicotine
  • Middle Aged
  • Microsomes
  • Methadone
  • Male
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Bloom, A. J., Wang, P.-F., & Kharasch, E. D. (2019). Nicotine oxidation by genetic variants of CYP2B6 and in human brain microsomes. Pharmacol Res Perspect, 7(2), e00468. https://doi.org/10.1002/prp2.468
Bloom, Adam Joseph, Pan-Fen Wang, and Evan D. Kharasch. “Nicotine oxidation by genetic variants of CYP2B6 and in human brain microsomes.Pharmacol Res Perspect 7, no. 2 (April 2019): e00468. https://doi.org/10.1002/prp2.468.
Bloom AJ, Wang P-F, Kharasch ED. Nicotine oxidation by genetic variants of CYP2B6 and in human brain microsomes. Pharmacol Res Perspect. 2019 Apr;7(2):e00468.
Bloom, Adam Joseph, et al. “Nicotine oxidation by genetic variants of CYP2B6 and in human brain microsomes.Pharmacol Res Perspect, vol. 7, no. 2, Apr. 2019, p. e00468. Pubmed, doi:10.1002/prp2.468.
Bloom AJ, Wang P-F, Kharasch ED. Nicotine oxidation by genetic variants of CYP2B6 and in human brain microsomes. Pharmacol Res Perspect. 2019 Apr;7(2):e00468.

Published In

Pharmacol Res Perspect

DOI

EISSN

2052-1707

Publication Date

April 2019

Volume

7

Issue

2

Start / End Page

e00468

Location

United States

Related Subject Headings

  • Tobacco Use Disorder
  • Stereoisomerism
  • Recombinant Proteins
  • Polymorphism, Single Nucleotide
  • Oxidation-Reduction
  • Nicotine
  • Middle Aged
  • Microsomes
  • Methadone
  • Male