Association analysis of CYP2A6 genotypes and haplotypes with 5-fluorouracil formation from tegafur in human liver microsomes

Pharmacogenomics. 2011 Apr;12(4):481-92. doi: 10.2217/pgs.10.202.


Aim: Tegafur is primarily converted to 5-fluorouracil (5-FU) by CYP2A6 in the human liver to exert its antitumor effect. Our objective was to comprehensively investigate the effects of CYP2A6 genetic polymorphisms on tegafur bioactivation activity.

Materials & methods: Using a set of over 45 Chinese livers, the association between CYP2A6 genetic variations and 5-FU formation rates from tegafur, as well as CYP2A6 mRNA and protein levels, was determined.

Results: A total of 20 polymorphic variants and 20 haplotypes of CYP2A6 were identified. From genotype/haplotype-phenotype association tests, we demonstrated that CYP2A6*4 was the main allele responsible for the decreased 5-FU formation from tegafur and CYP2A6 expression in this population. By contrast, haplotype 14 (a novel CYP2A6*1B allele) was associated with increased microsomal 5-FU formation activity and CYP2A6 expression, and this may be attributed to the combined effects of three single variants (g.22C>T, g.1620T>C and a gene conversion in the 3´-UTR) included in this haplotype.

Conclusion: We concluded that CYP2A6*4 and the novel CYP2A6*1B variant were the major genetic determinants of interindividual variability in 5-FU formation from tegafur in Chinese livers. Original submitted 2 November 2010; Revision submitted 3 December 2010.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Alleles
  • Antimetabolites, Antineoplastic / pharmacokinetics*
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Child
  • Cytochrome P-450 CYP2A6
  • Female
  • Fluorouracil / metabolism*
  • Genotype
  • Haplotypes / genetics
  • Humans
  • Male
  • Microsomes, Liver / enzymology*
  • Middle Aged
  • Polymorphism, Genetic
  • Tegafur / pharmacokinetics*
  • Young Adult


  • Antimetabolites, Antineoplastic
  • Tegafur
  • Aryl Hydrocarbon Hydroxylases
  • CYP2A6 protein, human
  • Cytochrome P-450 CYP2A6
  • Fluorouracil