Compendium of gene expression profiles comprising a baseline model of the human liver drug metabolism transcriptome
Compendium of gene expression profiles comprising a baseline model of the human liver drug metabolism transcriptome
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DOI：
10.1080/00498250600861728
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发表时间：
2006-10-01
期刊：
影响因子：
1.8
通讯作者：
Ulrich, R. G.
中科院分区：
文献类型：
--
作者：
Slatter, J. G.;Templeton, I. E.;Ulrich, R. G.
应用寡核苷酸芯片研究了75例正常人肝脏药物动力学和药物代谢(PKDM)相关基因表达的变异。目的是定义并利用吸收、分布、代谢和排泄(ADME)基因表达的变异性来识别共调控基因和潜在的可诱导基因表达的替代生物标志物。从供体组织制备RNA，并在Agilent微阵列上与来自所有供体的RNA质量平衡池进行杂交。PKDM基因集的聚集揭示了捐赠者具有不同的基因表达模式，这些基因将已知受核受体--孕烷X受体(PXR)调控的基因分组。来自不同人类种群的折叠范围度量和频率分布被用来定义75个人类肝脏中单个PKDM基因的变异性，并通过比较近交系和饮食/环境控制的27只恒河猴肝脏中的基础ADME基因表达变异性来将其置于背景中。肝转录组中变异最大的基因主要与药物代谢、中间代谢、炎症和细胞周期调控有关。75个可诱导的ADME基因表达的独特模式使它们的表达与许多其他基因的表达相关。AhR、CAR和PXR反应基因(CYP1A2、CYP2B6和CYP3A4)的相关基因可能是共同调控的，从而为识别诱导CYP的替代基因或蛋白提供了线索。综上所述，基因芯片被用来确定肝脏ADME基因在不同人群中的可变表达，ADME基因的表达变异性与近交系猕猴种群中的表达变异性进行了比较，并确定了可能与重要的诱导CYP基因共同调节的基因。
Oligonucleotide microarrays were used to study the variability of pharmacokinetics and drug metabolism (PKDM)-related gene expression in 75 normal human livers. The objective was to define and use absorption, distribution, metabolism and excretion (ADME) gene expression variability to discern co-regulated genes and potential surrogate biomarkers of inducible gene expression. RNA was prepared from donor tissue and hybridized on Agilent microarrays against an RNA mass balanced pool from all donors. Clustering of PKDM gene sets revealed donors with distinct patterns of gene expression that grouped genes known to be regulated by the nuclear receptor, pregnane X-receptor (PXR). Fold range metrics and frequency distributions from the heterogeneous human population were used to define the variability of individual PKDM genes in the 75 human livers and were placed in context by comparing expression data with basal ADME gene expression variability in an inbred and diet/environment controlled population of 27 Rhesus livers. The most variable genes in the hepatic transcriptome were mainly related to drug metabolism, intermediary metabolism, inflammation and cell cycle control. Unique patterns of expression across 75 individuals of inducible ADME gene expression allowed their expression to be correlated with the expression of many other genes. Correlated genes for AhR, CAR and PXR responsive genes (CYP1A2, CYP2B6 and CYP3A4) were identified that may be co-regulated and, therefore, provide clues to the identity of surrogate gene or protein markers for CYP induction. In conclusion, microarrays were used to define the variable expression of hepatic ADME genes in a diverse human population, the expression variability of ADME genes was compared with the expression variability in an inbred population of Rhesus monkeys, and genes were defined that may be co-regulated with important inducible CYP genes.