European journal of clinical pharmacology · 2009
Hepatic CYP2A6 levels and nicotine metabolism: impact of genetic, physiological, environmental, and epigenetic factors.
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Al Koudsi Nael, Hoffmann Ewa B, Assadzadeh Abbas, Tyndale Rachel F
Аннотация
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.
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.
Предметные рубрики MeSH
AdolescentAdultAge FactorsAryl Hydrocarbon HydroxylasesChi-Square DistributionChildChild, PreschoolCpG IslandsCytochrome P-450 CYP2A6DNA MethylationDexamethasoneEpigenesis, GeneticFemaleGene Expression Regulation, EnzymologicGenotypeHep G2 CellsHepatocytesHumansKineticsLinear ModelsLiverMaleMicrosomes, LiverMiddle AgedNicotineOxidation-ReductionPhenobarbitalPhenotypeRNA, MessengerSex FactorsYoung Adult