Gene-gene interactions between CYP2B6 and CYP2A6 in nicotine metabolism.
OBJECTIVE
CYP2A6 is the major enzyme involved in nicotine metabolism, yet large interindividual variations in the rate of nicotine metabolism exist within groups of individuals having the same CYP2A6 genotype. We investigated the influence of genetic variation in another potential nicotine-metabolizing enzyme, CYP2B6, and its interaction with CYP2A6, on the metabolism of nicotine.


METHODS
Two hundred and twelve healthy Caucasian adult twin volunteers underwent an intravenous infusion of stable isotope-labeled nicotine and its major metabolite, cotinine, for characterization of pharmacokinetic and metabolism phenotypes. Five CYP2B6 genetic polymorphisms causing amino acid substitutions (R22C, Q172 H, S259R, K262R, and R487C) were analyzed.


RESULTS
We observed that the CYP2B6*6 haplotype (defined as having both Q172 H and K262R variants) was associated with faster nicotine and cotinine clearance, and that such associations were more prominent among individuals having decreased-activity CYP2A6 genotypes. Statistically significant interactions between CYP2B6 and CYP2A6 genotypes were observed (P<0.003 for nicotine clearance and P<0.002 for cotinine clearance).


CONCLUSIONS
Our results indicate that CYP2B6 genetic variation is associated with the metabolism of nicotine and cotinine among individuals with decreased CYP2A6 activity. Further investigation of the roles of CYP2B6 and the interaction between CYP2B6 and CYP2A6 genotypes in mediating nicotine dependence and tobacco-related diseases is merited.
Ring
Huijun Z
HZ
Center for Health Sciences, SRI International, Menlo Park, CA, USA. huijun1@yahoo.com
Valdes
Ana M
AM
Nishita
Denise M
DM
Prasad
Suman
S
Jacob
Peyton
P
Tyndale
Rachel F
RF
Swan
Gary E
GE
Benowitz
Neal L
NL
D000328:Adult; D019943:Amino Acid Substitution; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D003367:Cotinine / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism*; D009538:Nicotine / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics* / Q000378:metabolism*; D010597:Pharmacogenetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D014429:Twins, Dizygotic / Q000235:genetics / Q000378:metabolism; D014430:Twins, Monozygotic / Q000235:genetics / Q000378:metabolism
D009538:Nicotine; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; C585599:CYP2B6 protein, human; D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; D003367:Cotinine