Allelic expression imbalance of the human CYP3A4 gene and individual phenotypic status
Allelic expression imbalance of the human CYP3A4 gene and individual phenotypic status
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DOI：
10.1093/hmg/ddh313
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发表时间：
2004-12-01
影响因子：
3.5
通讯作者：
Otsubo, K
中科院分区：
文献类型：
--
作者：
Hirota, T;Ieiri, I;Otsubo, K
人类细胞色素P450 3A4 （CYP3A4）在许多临床有用药物的代谢中起主导作用。这种酶的活性或表达的改变可能是药物反应性和毒性变化的主要原因。然而，人们普遍认为，大多数已知的编码和5'侧翼区域的单核苷酸多态性并不是CYP3A4表达和活性的大个体间差异的主要决定因素。我们发现等位基因变异在决定个体总肝脏CYP3A4 mRNA水平和代谢能力方面至关重要。CYP3A4 mRNA总水平与等位基因表达比存在一定的相关性，这是由两个等位基因得出的相对转录水平比。低表达率的个体，表现出两个等位基因之间的转录水平差异很大，表明肝脏CYP3A4 mRNA总量极低，因此通过睾酮6 β -羟基化评估的代谢能力较低。这些结果为个体化cyp3a4依赖性药物治疗和表达失衡对人类表型多样性的重要性提供了新的见解。
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.