细胞色素P450基因和核受体的苯巴比妥反应元件

Phenobarbital response elements of cytochrome P450 genes and nuclear receptors.

作者信息

Sueyoshi T, Negishi M

机构信息

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.

出版信息

Annu Rev Pharmacol Toxicol. 2001;41:123-43. doi: 10.1146/annurev.pharmtox.41.1.123.

DOI:10.1146/annurev.pharmtox.41.1.123

PMID:11264453

Abstract

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.

摘要

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。