title: Association analysis of CYP2A6 genotypes and haplotypes with 5-fluorouracil formation from tegafur in human liver microsomes.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, 229 North Taibai Road, Xi'an 710069, China.
authors.forename: Huijuan
authors.initials: H
authors.lastname: Wang
authors.forename: Ting
authors.initials: T
authors.lastname: Bian
authors.forename: Duan
authors.initials: D
authors.lastname: Liu
authors.forename: Tianbo
authors.initials: T
authors.lastname: Jin
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.forename: Aifen
authors.initials: A
authors.lastname: Lin
authors.forename: Chao
authors.initials: C
authors.lastname: Chen
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002648:Child; D065637:Cytochrome P-450 CYP2A6; D005260:Female; D005472:Fluorouracil / Q000378:metabolism*; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D008875:Middle Aged; D011110:Polymorphism, Genetic; D005641:Tegafur / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000964:Antimetabolites, Antineoplastic; D005641:Tegafur; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D005472:Fluorouracil