Expression of constitutive androstane receptor, hepatic nuclear factor 4α, and P450 oxidoreductase genes determines interindividual variability in basal expression and activity of a broad scope of xenobiotic metabolism genes in the human liver
Expression of constitutive androstane receptor, hepatic nuclear factor 4α, and P450 oxidoreductase genes determines interindividual variability in basal expression and activity of a broad scope of xenobiotic metabolism genes in the human liver
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DOI：
10.1124/dmd.107.016436
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发表时间：
2007-09-01
影响因子：
3.9
通讯作者：
Wan, Yu-Jui Yvonne
中科院分区：
文献类型：
--
作者：
Wortham, Matthew;Czerwinski, Maciej;Wan, Yu-Jui Yvonne
识别预测各种处方药清除率的遗传变异可能导致具有成本效益的个性化医疗。在这里，我们确定了调节基因，其在个体中的可变表达水平可能对各种药物的清除率有广泛的影响。对20个CYP3A活性可变的肝脏样本进行异种代谢基因及其调控基因的表达水平和活性分析。鉴定出外源代谢基因表达水平共线性程度最高的调控基因可能是药物清除率的主调控基因。CYP2A6、CYP2B6、CYP2C8、CYP2C9、CYP2C19、MRP2、OATP2、P450氧化还原酶（POR）和udp -葡萄糖醛酸糖基转移酶1A1 mRNA水平之间存在显著的线性相关（p < 0.05），表明这些外源代谢基因在转录水平上共同调控。通过偏回归分析，确定了组成型雄甾烷受体（CAR）和肝核因子4 α (HNF4 α)是表达水平与共调控外源代谢基因表达最密切相关的核受体。POR表达水平也与CAR和HNF4 α表达水平相关，与许多细胞色素P450的活性密切相关。因此，CAR、HNF4 α和POR表达水平的个体间差异可能决定了广泛的外源代谢基因的表达和活性变化，从而决定了各种外源代谢的清除率。鉴定这些候选主调控基因的多态性，解释它们在个体之间的可变表达，可能会产生易于检测的生物标志物，可以作为异种生物清除率的预测因子。
Identification of genetic variation predictive of clearance rate of a wide variety of prescription drugs could lead to cost-effective personalized medicine. Here we identify regulatory genes whose variable expression level among individuals may have widespread effects upon clearance rate of a variety of drugs. Twenty liver samples with variable CYP3A activity were profiled for expression level and activity of xenobiotic metabolism genes as well as genes involved in the regulation thereof. Regulatory genes whose expression level accounted for the highest degree of collinearity among expression levels of xenobiotic metabolism genes were identified as possible master regulators of drug clearance rate. Significant linear correlations ( p < 0.05) were identified among mRNA levels of CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, MRP2, OATP2, P450 oxidoreductase (POR), and UDP-glucuronosyltranferase 1A1, suggesting that these xenobiotic metabolism genes are coregulated at the transcriptional level. Using partial regression analysis, constitutive androstane receptor ( CAR) and hepatic nuclear factor 4 alpha( HNF4 alpha) were identified as the nuclear receptors whose expression levels are most strongly associated with expression of coregulated xenobiotic metabolism genes. POR expression level, which is also associated with CAR and HNF4 alpha expression level, was found to be strongly associated with the activity of many cytochromes P450. Thus, interindividual variation in the expression level of CAR, HNF4 alpha, and POR probably determines variation in expression and activity of a broad scope of xenobiotic metabolism genes and, accordingly, clearance rate of a variety of xenobiotics. Identification of polymorphisms in these candidate master regulator genes that account for their variable expression among individuals may yield readily detectable biomarkers that could serve as predictors of xenobiotic clearance rate.