Human Molecular Genetics Advance Access originally published online on September 30, 2004
Human Molecular Genetics 2004 13(23):2959-2969; doi:10.1093/hmg/ddh313
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Human Molecular Genetics, Vol. 13, No. 23 © Oxford University Press 2004; all rights reserved
Allelic expression imbalance of the human CYP3A4 gene and individual phenotypic status
1Clinical Pharmacokinetics, Division of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 8128582, Japan, 2Department of Hospital Pharmacy, Faculty of Medicine, 3Division of Functional Genomics, Research Center for Bioscience and Technology and 4Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, Yonago 6838504, Japan and 5Laboratory of Biochemical Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 2740816, Japan
Received August 6, 2004; Accepted September 20, 2004
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 6ß-hydroxylation. These results present a new insight into the individualized CYP3A4-dependent pharmacotherapy and the importance of expression imbalance to human phenotypic diversity.
* To whom correspondence should be addressed at: Department of Hospital Pharmacy, Faculty of Medicine, Tottori University, Nishi-machi 36-1, Yonago 6838504, Japan. Tel: +81 859348385; Fax: +81 859348087; Email: ieiri{at}grape.med.tottori-u.ac.jp
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  H. Khatib, V. Schutzkus, Y. M. Chang, and G. J. M. Rosa Pattern of Expression of the Uterine Milk Protein Gene and its Association with Productive Life in Dairy Cattle J Dairy Sci, May 1, 2007; 90(5): 2427 - 2433. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Milani, M. Gupta, M. Andersen, S. Dhar, M. Fryknas, A. Isaksson, R. Larsson, and A.-C. Syvanen Allelic imbalance in gene expression as a guide to cis-acting regulatory single nucleotide polymorphisms in cancer cells Nucleic Acids Res., March 12, 2007; 35(5): e34 - e34. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Sadee and Z. Dai Pharmacogenetics/genomics and personalized medicine Hum. Mol. Genet., October 15, 2005; 14(suppl_2): R207 - R214. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zhang, D. Wang, A. D. Johnson, A. C. Papp, and W. Sadee Allelic Expression Imbalance of Human mu Opioid Receptor (OPRM1) Caused by Variant A118G J. Biol. Chem., September 23, 2005; 280(38): 32618 - 32624. [Abstract] [Full Text] [PDF]
|
|