van Schaik Ron H N, van der Heiden Ilse P, van den Anker John N, Lindemans Jan
Department of Clinical Chemistry, Sophia Children's Hospital, Erasmus MC, 3000 CA Rotterdam, The Netherlands.
Clin Chem. 2002 Oct;48(10):1668-71.
Enzymes of the cytochrome P450 3A (CYP3A) family are responsible for the metabolism of >50% of currently prescribed drugs. CYP3A5 is expressed in a limited number of individuals. The absence of CYP3A5 expression in approximately 70% of Caucasians was recently correlated to a genetic polymorphism (CYP3A5*3). Because CYP3A5 may represent up to 50% of total CYP3A protein in individuals polymorphically expressing CYP3A5, it may have a major role in variation of CYP3A-mediated drug metabolism. Using sequencing, have been identified (Hustert et al. Pharmacogenetics 2001;11:773-9; Kuehl et al. Nat Genet 2001;27:383-91) variant alleles *2 through *7 for CYP3A5. Detection of CYP3A5 variant alleles, and knowledge about their allelic frequency in specific ethnic groups, is important to establish the clinical relevance of screening for these polymorphisms to optimize pharmacotherapy.
In a group of 500 healthy Dutch Caucasian blood donors, we determined the allelic frequency of the CYP3A5*2, *3, *4, *5, *6, and *7 alleles by use of newly developed PCR-restriction fragment length polymorphism assays.
The frequency of the defective CYP3A53 allele in the Dutch Caucasian population was 91%, followed by the CYP3A52 (1%) and CYP3A56 (0.1%) alleles. The CYP3A54, *5, and *7 alleles were not detected.
On the basis of its allelic frequency, screening for the CYP3A53 allele in the Caucasian population is extremely relevant. In addition, screening for the CYP3A52 allele may be taken into consideration in individuals heterozygous for the CYP3A53 allele. The CYP3A54, *5, *6, and *7 alleles have low allelic frequencies that do not support initial screening.
细胞色素P450 3A（CYP3A）家族的酶负责代谢目前超过50%的处方药。CYP3A5仅在少数个体中表达。最近发现，约70%的白种人缺乏CYP3A5表达与一种基因多态性（CYP3A53）有关。由于在多态性表达CYP3A5的个体中，CYP3A5可能占CYP3A总蛋白的50%，它可能在CYP3A介导的药物代谢变异中起主要作用。通过测序已鉴定出（Hustert等人，《药物遗传学》2001年；11：773 - 9；Kuehl等人，《自然遗传学》2001年；27：383 - 91）CYP3A5的2至*7变异等位基因。检测CYP3A5变异等位基因及其在特定种族群体中的等位基因频率，对于确定筛查这些多态性以优化药物治疗的临床相关性很重要。
在一组500名健康的荷兰白种人献血者中，我们使用新开发的聚合酶链反应 - 限制性片段长度多态性分析方法确定了CYP3A5*2、*3、*4、*5、6和7等位基因的等位基因频率。
荷兰白种人群中缺陷型CYP3A53等位基因的频率为91%，其次是CYP3A52（1%）和CYP3A56（0.1%）等位基因。未检测到CYP3A54、5和7等位基因。
基于其等位基因频率，在白种人群中筛查CYP3A53等位基因极具相关性。此外，对于CYP3A53等位基因杂合的个体，可考虑筛查CYP3A52等位基因。CYP3A54、*5、6和7等位基因的等位基因频率较低，不支持进行初步筛查。
