Lamba Jatinder K, Lin Yvonne S, Thummel Kenneth, Daly Ann, Watkins Paul B, Strom Stephen, Zhang Jiong, Schuetz Erin G
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Pharmacogenetics. 2002 Mar;12(2):121-32. doi: 10.1097/00008571-200203000-00006.
Marked interindividual variability in expression of CYP3A4 influences the disposition of many endo- and xenobiotics, including the metabolism of steroids, environmental toxins and therapeutically useful drugs. The present study was designed to determine the genetic basis of CYP3A4 variability. We analysed DNA from 82 individuals with known CYP3A4 phenotype including 53 Caucasians and 21 African-American liver donors, seven individuals who were outliers in CYP3A4 metabolism and five individuals in a family of a poor nifedipine metabolizer. In addition, we analysed DNA from the eight person DNA Polymorphism Discovery Resource subset (Coriell Institute) and 89 individuals representing nine ethnic groups. Five non-synonymous mutations in the coding region of CYP3A4 were observed. CYP3A414 (T44C) in exon 1 resulted in an L15P change; CYP3A415 (G14387A) in exon 6 resulted in a R162Q substitution; CYP3A410 (G14422C) in exon 6 resulted in a D174H substitution; CYP3A416 (C15721G) in exon 7 resulted in a T185S amino acid substitution; and CYP3A4*12 (C22002T) in exon 11 resulted in a L373F change in the CYP3A4 protein. An additional six single nucleotide polymorphisms (SNPs) in the 5'-UTR, 13 SNPs in the introns and three SNPs in the 3'-UTR were observed. Extensive population differences were observed in the frequencies of various CYP3A4 alleles. None of the 28 CYP3A4 SNPs identified in CYP3A4 phenotyped persons (most individuals being heterozygous for any CYP3A4 variant) was associated with low hepatic CYP3A4 protein expression or low CYP3A4 activity in vivo.
CYP3A4表达存在显著的个体间差异，这会影响许多内源性和外源性物质的处置，包括类固醇、环境毒素和治疗性药物的代谢。本研究旨在确定CYP3A4变异性的遗传基础。我们分析了82名已知CYP3A4表型个体的DNA，其中包括53名白种人和21名非裔美国肝脏供体、7名CYP3A4代谢异常个体以及硝苯地平代谢不良者家族中的5名个体。此外，我们还分析了来自八人DNA多态性发现资源子集（科里尔研究所）的DNA以及代表九个种族群体的89名个体的DNA。在CYP3A4编码区观察到五个非同义突变。外显子1中的CYP3A414（T44C）导致L15P改变；外显子6中的CYP3A415（G14387A）导致R162Q替代；外显子6中的CYP3A410（G14422C）导致D174H替代；外显子7中的CYP3A416（C15721G）导致T185S氨基酸替代；外显子11中的CYP3A4*12（C22002T）导致CYP3A4蛋白中的L373F改变。在5'-UTR中还观察到另外六个单核苷酸多态性（SNP）、内含子中的13个SNP以及3'-UTR中的三个SNP。在各种CYP3A4等位基因的频率上观察到广泛的人群差异。在CYP3A4表型个体中鉴定出的28个CYP3A4 SNP（大多数个体对任何CYP3A4变体均为杂合子）均与肝脏CYP3A4蛋白低表达或体内CYP3A4低活性无关。
