A novel CYP2A6 allele (CYP2A6*35) resulting in an amino-acid substitution (Asn438Tyr) is associated with lower CYP2A6 activity in vivo.
Cytochrome P450 2A6 (CYP2A6) is the primary human enzyme involved in nicotine metabolism. The objective of this study was to characterize two nonsynonymous single nucleotide polymorphisms in CYP2A6(*)24, 594G>C (Val110Leu) and 6458A>T (Asn438Tyr). We determined their haplotype, allele frequencies, effect on CYP2A6 activity in vivo, as well as their stability and ability to metabolize nicotine in vitro. CYP2A6(*)35 (6458A>T) occurred at a frequency of 2.5-2.9% among individuals of black African descent, 0.5-0.8% among Asians and was not found in Caucasians. In addition, we identified two novel alleles, CYP2A6(*)36 (6458A>T and 6558T>C (Ile471Thr)) and CYP2A6(*)37 (6458A>T, 6558T>C and 6600G>T (Arg485Leu)). In vivo, CYP2A6(*)35 was associated with lower CYP2A6 activity as measured by the 3HC/COT ratio. In vitro, CYP2A6.35 had decreased nicotine C-oxidation activity and thermal stability. In conclusion, we identified three novel CYP2A6 alleles (CYP2A6(*)35, (*)36 and (*)37); the higher allele frequency variant CYP2A6(*)35 was associated with lower CYP2A6 activity.
Al Koudsi
Nael
N
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
Ahluwalia
Jasjit S
JS
Lin
Shih-Ku
SK
Sellers
Edward M
EM
Tyndale
Rachel F
RF
D019943:Amino Acid Substitution; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D044466:Asian People / Q000235:genetics; D044383:Black People / Q000235:genetics; D065637:Cytochrome P-450 CYP2A6; D004795:Enzyme Stability; D005787:Gene Frequency; D006801:Humans; D007700:Kinetics; D009538:Nicotine / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
D009538:Nicotine; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6