A novel CYP2A6 allele (CYP2A6*35) resulting in an amino-acid substitution (Asn438Tyr) is associated with lower CYP2A6 activity in vivo

Pharmacogenomics J. 2009 Aug;9(4):274-82. doi: 10.1038/tpj.2009.11. Epub 2009 Apr 14.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Asians / genetics
  • Blacks / genetics
  • Cytochrome P-450 CYP2A6
  • Enzyme Stability
  • Gene Frequency
  • Humans
  • Kinetics
  • Nicotine / metabolism
  • Polymorphism, Single Nucleotide
  • Whites / genetics

Substances

  • Nicotine
  • Aryl Hydrocarbon Hydroxylases
  • CYP2A6 protein, human
  • Cytochrome P-450 CYP2A6