Sueyoshi T, Negishi M
Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Annu Rev Pharmacol Toxicol. 2001;41:123-43. doi: 10.1146/annurev.pharmtox.41.1.123.
Phenobarbital (PB) response elements are composed of various nuclear receptor (NR)-binding sites. A 51-bp distal element PB-responsive enhancer module (PBREM) conserved in the PB-inducible CYP2B genes contains two NR-binding direct repeat (DR)-4 motifs. Responding to PB exposure in liver, the NR constitutive active receptor (CAR) translocates to the nucleus, forms a dimer with the retinoid X receptor (RXR), and activates PBREM via binding to DR-4 motifs. For CYP3A genes, a common NR site [DR-3 or everted repeat (ER)-6] is present in proximal promoter regions. In addition, the distal element called the xenobiotic responsive module (XREM) is found in human CYP3A4 genes, which contain both DR-3 and ER-6 motifs. Pregnane X receptor (PXR) could bind to all of these sites and, upon PB induction, a PXR:RXR heterodimer could transactivate XREM. These response elements and NRs are functionally versatile, and capable of responding to distinct but overlapping groups of xenochemicals.
苯巴比妥（PB）反应元件由各种核受体（NR）结合位点组成。在PB诱导的CYP2B基因中保守的一个51碱基对的远端元件PB反应增强子模块（PBREM）包含两个NR结合直接重复（DR）-4基序。在肝脏中对PB暴露作出反应时，NR组成型活性受体（CAR）易位至细胞核，与视黄酸X受体（RXR）形成二聚体，并通过与DR-4基序结合来激活PBREM。对于CYP3A基因，近端启动子区域存在一个常见的NR位点[DR-3或反向重复（ER）-6]。此外，在人CYP3A4基因中发现了称为外源性物质反应模块（XREM）的远端元件，其包含DR-3和ER-6基序。孕烷X受体（PXR）可与所有这些位点结合，并且在PB诱导后，PXR:RXR异二聚体可反式激活XREM。这些反应元件和NR在功能上具有多样性，并且能够对不同但重叠的外源性化学物质组作出反应。
