title: CYP3A4*1G regulates CYP3A4 intron 10 enhancer and promoter activity in an allelic-dependent manner.
abstract: OBJECTIVE
  CYP3A4*1G (G > A) in human CYP3A4 intron 10 is associated with therapeutic effects of CYP3A4-metabolized drugs. The aim of this study was to predict its function in the regulation of CYP3A4 expression.
  
  
  METHODS
  Functional analysis of the CYP3A4*1G allele was performed using bioinformatic methods and enhancer or promoter reporter assays in HepG2 cells.
  
  
  RESULTS
  Transcription regulatory elements like CAATboxes, TATA-boxes, Sp1, SMARCA3.01, and Box II-like sequence were present in the intron 10 of CYP3A4. SMARCA3.01 and Box II-like sequence were responsible for differential binding of transcription factors on the CYP3A4*1G allele. In CYP3A4*1G, the G allele enhanced expression of the CYP3A4 promoter in a position-dependent and orientation-dependent manner, however, the A allele enhanced expression of the CYP3A4 promoter in a position-independent and orientation-independent manner. In addition, the G allele and the A allele both displayed strong transcriptional activation, but the latter showed higher promoter activity than the former. Also, the A allele showed greater activity than the CYP3A4 promoter.
  
  
  CONCLUSIONS
  These results in vitro suggest that CYP3A4*1G regulates CYP3A4 intron 10 enhancer and promoter activity in an allelic-dependent manner.
authors.forename: Weihong
authors.initials: W
authors.lastname: Yang
authors.forename: Dengzhi
authors.initials: D
authors.lastname: Zhao
authors.forename: Shengna
authors.initials: S
authors.lastname: Han
authors.forename: Zengyuan
authors.initials: Z
authors.lastname: Tian
authors.forename: Liang
authors.initials: L
authors.lastname: Yan
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Zhao
authors.forename: Quancheng
authors.initials: Q
authors.lastname: Kan
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Lirong
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000483:Alleles; D001483:Base Sequence; D001665:Binding Sites; D019295:Computational Biology; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D005838:Genotype; D056945:Hep G2 Cells; D006801:Humans; D007438:Introns; D008969:Molecular Sequence Data; D010641:Phenotype; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D014157:Transcription Factors; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human