Two linked mutations in transcriptional regulatory elements of the CYP3A5 gene constitute the major genetic determinant of polymorphic activity in humans

Pharmacogenetics. 2000 Jul;10(5):415-24. doi: 10.1097/00008571-200007000-00005.


Cytochrome P450 3A subfamily members (CYP3A) are the most abundant liver cytochrome P450 forms, responsible for the biotransformation of over 50% of all drugs. The expression and activity of isoforms CYP3A4 and CYP3A5 show wide inter-individual variation, influencing both drug response and disease susceptibility. The molecular basis for this variation has never been defined. In this study, we used midazolam to characterize CYP3A5 phenotype in a panel of liver samples. A clear bimodality in metabolism was observed. Analysis of the 5' flanking region of the CYP3A5 gene identified two linked polymorphisms, T-369G and A-45G, located in transcriptional regulatory elements which are associated with increased expression and activity of the gene. A polymerase chain reaction based detection assay is described facilitating future studies into both the metabolic consequences of this variation and disease association studies relating to CYP3A5.

MeSH terms

  • 5' Untranslated Regions / analysis
  • Alleles
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / analysis
  • Cytochrome P-450 Enzyme System / biosynthesis
  • Cytochrome P-450 Enzyme System / genetics*
  • Cytochrome P-450 Enzyme System / metabolism*
  • Gene Frequency
  • Genetic Linkage*
  • Genetic Variation
  • Humans
  • Isoenzymes / analysis
  • Isoenzymes / biosynthesis
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Microsomes, Liver / enzymology
  • Midazolam / metabolism
  • Mutation / genetics*
  • Phenotype
  • Polymorphism, Genetic*
  • RNA, Messenger / biosynthesis
  • Regulatory Sequences, Nucleic Acid / genetics*
  • Transcription, Genetic*


  • 5' Untranslated Regions
  • Isoenzymes
  • RNA, Messenger
  • Cytochrome P-450 Enzyme System
  • CYP3A protein, human
  • CYP3A5 protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Midazolam