Hepatic CYP2A6 levels and nicotine metabolism: impact of genetic, physiological, environmental, and epigenetic factors

Eur J Clin Pharmacol. 2010 Mar;66(3):239-51. doi: 10.1007/s00228-009-0762-0. Epub 2009 Dec 9.


Purpose: We investigated the role of genetic, physiological, environmental, and epigenetic factors in regulating CYP2A6 expression and nicotine metabolism.

Methods: Human livers (n = 67) were genotyped for CYP2A6 alleles and assessed for nicotine metabolism and CYP2A6 expression (mRNA and protein). In addition, a subset of livers (n = 18), human cryopreserved hepatocytes (n = 2), and HepG2 cells were used for DNA methylation analyses.

Results: Liver samples with variant CYP2A6 alleles had significantly lower CYP2A6 protein expression, nicotine C-oxidation activity, and affinity for nicotine. Female livers had significantly higher CYP2A6 protein and mRNA expression compared to male livers. Livers exposed to dexamethasone and phenobarbital had higher CYP2A6 expression and activity, however the difference was not statistically significant. Age and DNA methylation status of the CpG island and a regulatory site were not associated with altered CYP2A6.

Conclusions: We identified genotype, gender, and exposure to inducers as sources of variation in CYP2A6 expression and activity, but much variation remains to be accounted for.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age Factors
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Chi-Square Distribution
  • Child
  • Child, Preschool
  • CpG Islands
  • Cytochrome P-450 CYP2A6
  • DNA Methylation
  • Dexamethasone / pharmacology
  • Epigenesis, Genetic* / drug effects
  • Female
  • Gene Expression Regulation, Enzymologic* / drug effects
  • Genotype
  • Hep G2 Cells
  • Hepatocytes / drug effects
  • Hepatocytes / enzymology*
  • Humans
  • Kinetics
  • Linear Models
  • Liver / drug effects
  • Liver / enzymology*
  • Male
  • Microsomes, Liver / enzymology
  • Middle Aged
  • Nicotine / metabolism*
  • Oxidation-Reduction
  • Phenobarbital / pharmacology
  • Phenotype
  • RNA, Messenger / metabolism
  • Sex Factors
  • Young Adult


  • RNA, Messenger
  • Nicotine
  • Dexamethasone
  • Aryl Hydrocarbon Hydroxylases
  • CYP2A6 protein, human
  • Cytochrome P-450 CYP2A6
  • Phenobarbital