Characterization of a novel CYP2A7/CYP2A6 hybrid allele (CYP2A6*12) that causes reduced CYP2A6 activity

Hum Mutat. 2002 Oct;20(4):275-83. doi: 10.1002/humu.10126.


The human CYP2A6 enzyme metabolizes certain drugs and pre-carcinogens and appears to be the most important enzyme for nicotine metabolism. At present, more than 10 different allelic variants are known that cause abolished or decreased enzyme activity. Genetic polymorphism in this gene might be of particular importance for an individual's need for nicotine and for susceptibility to lung and/or liver cancer. We have identified a new CYP2A6 allele (CYP2A6*12) which carries an unequal crossover between the CYP2A6 and CYP2A7 genes in intron 2. This results in a hybrid allele where the 5' regulatory region and exons 1-2 are of CYP2A7 origin and exons 3-9 are of CYP2A6 origin, resulting in 10 amino acid substitutions compared to the CYP2A6(*)1 allele. Phenotyping with the CYP2A6 substrate coumarin indicates that it causes reduced CYP2A6 activity in'vivo. Furthermore, when expressed in mammalian COS-1 cells, the enzyme variant catalyzed 7-hydroxylation of coumarin at a rate approximately 60% of that of the wild-type enzyme. The CYP2A6(*)12 allele was present at an allele frequency of 2.2% among Spaniards, but was absent in Chinese.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles*
  • Animals
  • Aryl Hydrocarbon Hydroxylases / biosynthesis
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Aryl Hydrocarbon Hydroxylases / metabolism*
  • Blotting, Southern / methods
  • COS Cells / metabolism
  • Cell Line
  • Chlorocebus aethiops
  • Coumarins / metabolism
  • Cytochrome P-450 CYP2A6
  • Cytochrome P450 Family 2
  • Female
  • Genotype
  • Humans
  • Isoenzymes / biosynthesis
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Male
  • Mixed Function Oxygenases / biosynthesis
  • Mixed Function Oxygenases / genetics*
  • Mixed Function Oxygenases / metabolism*
  • Pedigree
  • Phenotype
  • Polymerase Chain Reaction / methods
  • Recombination, Genetic / genetics
  • Sequence Analysis, DNA / methods
  • Substrate Specificity / genetics


  • Coumarins
  • Isoenzymes
  • coumarin
  • Mixed Function Oxygenases
  • Aryl Hydrocarbon Hydroxylases
  • CYP2A6 protein, human
  • CYP2A7 protein, human
  • Cytochrome P-450 CYP2A6
  • Cytochrome P450 Family 2