Allelic expression imbalance of the human CYP3A4 gene and individual phenotypic status

Hum Mol Genet. 2004 Dec 1;13(23):2959-69. doi: 10.1093/hmg/ddh313. Epub 2004 Sep 30.


The human cytochrome P450 3A4 (CYP3A4) plays a dominant role in the metabolism of numerous clinically useful drugs. Alterations in the activity or expression of this enzyme may account for a major part of the variation in drug responsiveness and toxicity. However, it is generally accepted that most of the known single nucleotide polymorphisms in the coding and 5'-flanking regions are not the main determinants for the large inter-individual variability of CYP3A4 expression and activity. We show that the allelic variation is critically involved in determining the individual total hepatic CYP3A4 mRNA level and metabolic capability. There exists a definite correlation between the total CYP3A4 mRNA level and allelic expression ratio, the relative transcript level ratio derived from the two alleles. Individuals with a low expression ratio, exhibiting a large difference of transcript level between the two alleles, revealed extremely low levels of total hepatic CYP3A4 mRNA, and thus low metabolic capability as assessed by testosterone 6beta-hydroxylation. These results present a new insight into the individualized CYP3A4-dependent pharmacotherapy and the importance of expression imbalance to human phenotypic diversity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles*
  • Base Sequence
  • CpG Islands
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / genetics*
  • DNA Primers
  • Humans
  • Liver / enzymology
  • Phenotype
  • Polymorphism, Single Nucleotide
  • RNA, Messenger / genetics


  • DNA Primers
  • RNA, Messenger
  • Cytochrome P-450 Enzyme System
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human