Department of Pharmacology, Universitätsmedizin, Johannes Gutenberg University, Mainz, Germany.
Pharmacogenet Genomics. 2010 Mar;20(3):167-78. doi: 10.1097/FPC.0b013e328336bbeb.
The individually variable and unpredictable expression of CYP3A4 compromises therapies with 50% of contemporary drugs. Gene variants explain only a fraction of this variability.
We investigated the evolution of CYP3A4 transcriptional regulation by nuclear receptors such as the xenobiotics sensors PXR and CAR.
The combination of a proximal ER6 element with XREM and CLEM represents the original scheme of CYP3A regulation by nuclear receptors in placental mammals. Among human CYP3A genes, this scheme is retained only in CYP3A4, whereas non-CYP3A4 genes lost these elements to a variable extent during primate evolution. In parallel, the number of elements outside XREM and CLEM potentially responsive to PXR and CAR increased in primate CYP3A4 orthologs, which led to enhanced CYP3A4 inducibility. Additions to the other primate CYP3A genes were more restricted and specific, as exemplified by a CYP3A5 DR4 site responsive to CAR, but not to PXR. All these changes resulted in human CYP3A4 having a much more complex upstream regulatory region in comparison to its paralogs.
Instead of gene variants, the intraindividual CYP3A4 expression variability in humans may be primarily caused by particular sensitivity of this gene to endogenous and exogenous PXR and CAR ligands conferred by the unique complexity of its upstream regulatory region.
CYP3A4 的个体可变性和不可预测性使 50%的当代药物的治疗受到影响。基因变异仅能解释其部分可变性。
我们研究了核受体（如外源传感器 PXR 和 CAR）对 CYP3A4 转录调控的演变。
近端 ER6 元件与 XREM 和 CLEM 的结合代表了核受体在胎盘哺乳动物中对 CYP3A 调节的原始方案。在人类 CYP3A 基因中，这种方案仅在 CYP3A4 中保留，而在灵长类动物进化过程中，非 CYP3A4 基因则不同程度地失去了这些元件。与此同时，XREM 和 CLEM 之外潜在响应 PXR 和 CAR 的元件数量在灵长类 CYP3A4 同源物中增加，这导致 CYP3A4 的诱导能力增强。对其他灵长类 CYP3A 基因的添加则更为局限和特定，例如 CYP3A5 的 DR4 位点对 CAR 有反应，但对 PXR 没有反应。所有这些变化导致人类 CYP3A4 的上游调控区比其同源物更为复杂。
与基因变异相比，人类 CYP3A4 的个体内表达可变性可能主要是由于其上游调控区的独特复杂性赋予了该基因对内源性和外源性 PXR 和 CAR 配体的特殊敏感性。
