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

Abstract:

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.

journal_name

Eur J Clin Pharmacol

authors

Al Koudsi N,Hoffmann EB,Assadzadeh A,Tyndale RF

doi

10.1007/s00228-009-0762-0

subject

Has Abstract

pub_date

2010-03-01 00:00:00

pages

239-51

issue

3

eissn

0031-6970

issn

1432-1041

journal_volume

66

pub_type

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