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

Takeshi Hirota, Ichiro Ieire, Hiroshi Takane, Shinji Maegawa, Masakiyo Hosokawa, Kaoru Kobayashi, Kan Chiba, Eiji Nanba, Mitsuo Oshimura, Tetsuo Sato, Shun Higuchi, Otsubo Kenji

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Abstract

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 6β -hydroxylation. These results present a new insight into the individualized CYP3A4-dependent pharmacotherapy and the importance of expression imbalance to human phenotypic diversity.

Original languageEnglish
Pages (from-to)2959-2969
Number of pages11
JournalHuman Molecular Genetics
Volume13
Issue number23
DOIs
Publication statusPublished - Dec 1 2004

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All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Hirota, T., Ieire, I., Takane, H., Maegawa, S., Hosokawa, M., Kobayashi, K., ... Kenji, O. (2004). Allelic expression imbalance of the human CYP3A4 gene and individual phenotypic status. Human Molecular Genetics, 13(23), 2959-2969. https://doi.org/10.1093/hmg/ddh313