An in vivo pilot study characterizing the new CYP2A6*7, *8, and *10 alleles.
We developed genotyping assays for CYP2A6*7 (Ile471Thr) and CYP2A6*8 (Arg485Leu). We found higher allelic frequencies in Japanese and Chinese versus Caucasians and identified an allele in which both substitutions occur together (CYP2A6*10). We created a homology model for predicting the impact of allelic variants on enzymatic activity and subsequently tested this in vivo in a pilot kinetic study. Consistent with our homology model predictions, we found (i) that CYP2A6*7 produces an enzyme that has decreased (not inactive) activity for metabolizing nicotine and coumarin; (ii) that CYP2A6*8 is unlikely to affect catalytic activity in vivo; and (iii) that having both substitutions together on an allele (CYP2A6*10) dramatically reduces function and may be fully inactive for some substrates. In conclusion, this study identifies, at relatively high frequency in Asians, an allele with decreased activity (may be substrate selective), a fully functional allele, and an allele containing both substitutions in which function is dramatically reduced.
Xu
C
C
Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Rao
Y S
YS
Xu
B
B
Hoffmann
E
E
Jones
J
J
Sellers
E M
EM
Tyndale
R F
RF
D000483:Alleles; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D044466:Asian People; D002681:China; D003367:Cotinine / Q000097:blood; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007564:Japan; D007700:Kinetics; D006899:Mixed Function Oxygenases / Q000235:genetics*; D008958:Models, Molecular; D009538:Nicotine / Q000097:blood; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D017422:Sequence Analysis, DNA; D013997:Time Factors; D014468:Umbelliferones / Q000097:blood; D044465:White People
D014468:Umbelliferones; C031477:7-hydroxycoumarin; D009538:Nicotine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D003367:Cotinine