Journal Article

Allelic expression imbalance of the human <i>CYP3A4</i> gene and individual phenotypic status

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

in Human Molecular Genetics

Volume 13, issue 23, pages 2959-2969
Published in print December 2004 | ISSN: 0964-6906
Published online September 2004 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddh313
Allelic expression imbalance of the human CYP3A4 gene and individual phenotypic status

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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.

Journal Article.  6721 words.  Illustrated.

Subjects: Genetics and Genomics

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