Human Molecular Genetics Advance Access published online on September 30, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh313
© 2004 by Oxford University Press
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1 Clinical Pharmacokinetics, Division of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, 8128582, Japan
* To whom correspondence should be addressed. E-mail: ieiri{at}grape.med.tottori-u.ac.jp.
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 6
Article
Allelic expression imbalance of the human CYP3A4 gene and individual phenotypic status
2 Department of Hospital Pharmacy, Faculty of Medicine, Graduate School of Medical Science, Tottori University, Nishi-machi 36-1, Yonago, 683-8504, Japan
3 Department of Hospital Pharmacy, Faculty of Medicine, Graduate School of Medical Science, Tottori University, Yonago, 6838504, Japan
4 Division of Functional Genomics, Research Center for Bioscience and Technology, Graduate School of Medical Science, Tottori University, Yonago, 6838504, Japan
5 Laboratory of Biochemical Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 2740816, Japan
6 Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, Yonago, 6838504, Japan
Abstract 
-hydroxylation. These results present a new insight into the individualized CYP3A4-dependent pharmacotherapy and the importance of expression imbalance to human phenotypic diversity.
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