人类孕烷X受体:基因组结构和识别自然等位变异和功能描述。
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张J,屈尔P,绿色ED, Touchman JW,沃特金斯PB,戴利,大厅SD, Maurel P, rel M,布莱墨C, Yasuda K, Wrighton SA,汉考克M, Kim RB斯特罗姆年代,Thummel K,罗素CG,哈德森JR Schuetz如Boguski女士
人类孕烷X受体:基因组结构和识别自然等位变异和功能描述。
药物基因学。2001年10月,11 (7):555 - 72。
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11668216 (在PubMed]
- 文摘
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孕烷X受体(PXR) /类固醇和异型生物质受体(SXR)转录激活细胞色素P4503A4 (CYP3A4)当配体激活endobiotics和外源性物质。我们克隆人类PXR基因和dna序列分析的个体CYP3A表型是已知的。PXR基因跨越35 kb,包含9个外显子,映射到而13 q11 - 13区段的染色体。38个单核苷酸多态性(snp)被确定包括六个snp的编码区。三个编码snp的非同义创造新的PXR等位基因(PXR * 2, p27 (79 c T);PXR * 3, G36R(106克);PXR * 4, R122Q(4321克)]。PXR * 2是0.20的频率在白种人的非洲裔美国人,也从来没有发现。肝CYP3A4蛋白质的表达没有明显不同的非裔美国人之间纯合PXR * 1相比PXR * 2等位基因。PXR * 4是一种罕见的变异中发现只有一个高加索人。 Homology modelling suggested that R122Q, (PXR*4) is a direct DNA contact site variation in the third alpha-helix in the DNA binding domain. Compared with PXR*1, and variants PXR*2 and PXR*3, only the variant PXR*4 protein had significantly decreased affinity for the PXR binding sequence in electromobility shift assays and attenuated ligand activation of the CYP3A4 reporter plasmids in transient transfection assays. However, the person heterozygous for PXR*4 is normal for CYP3A4 metabolism phenotype. The relevance of each of the 38 PXR SNPs identified in DNA of individuals whose CYP3A basal and rifampin-inducible CYP3A4 expression was determined in vivo and/or in vitro was demonstrated by univariate statistical analysis. Because ligand activation of PXR and upregulation of a system of drug detoxification genes are major determinants of drug interactions, it will now be useful to extend this work to determine the association of these common PXR SNPs to human variation in induction of other drug detoxification gene targets.