Blumberg B, Sabbagh W, Juguilon H, Bolado J, van Meter C M, Ong E S, Evans R M
Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Genes Dev. 1998 Oct 15;12(20):3195-205. doi: 10.1101/gad.12.20.3195.
An important requirement for physiologic homeostasis is the detoxification and removal of endogenous hormones and xenobiotic compounds with biological activity. Much of the detoxification is performed by cytochrome P-450 enzymes, many of which have broad substrate specificity and are inducible by hundreds of different compounds, including steroids. The ingestion of dietary steroids and lipids induces the same enzymes; therefore, they would appear to be integrated into a coordinated metabolic pathway. Instead of possessing hundreds of receptors, one for each inducing compound, we propose the existence of a few broad specificity, low-affinity sensing receptors that would monitor aggregate levels of inducers to trigger production of metabolizing enzymes. In support of this model, we have isolated a novel nuclear receptor, termed the steroid and xenobiotic receptor (SXR), which activates transcription in response to a diversity of natural and synthetic compounds. SXR forms a heterodimer with RXR that can bind to and induce transcription from response elements present in steroid-inducible cytochrome P-450 genes and is expressed in tissues in which these catabolic enzymes are expressed. These results strongly support the steroid sensor hypothesis and suggest that broad specificity sensing receptors may represent a novel branch of the nuclear receptor superfamily.
生理稳态的一个重要要求是对内源性激素和具有生物活性的外源性化合物进行解毒和清除。大部分解毒过程由细胞色素P - 450酶完成，其中许多酶具有广泛的底物特异性，并且可被数百种不同化合物诱导，包括类固醇。饮食中类固醇和脂质的摄入会诱导相同的酶；因此，它们似乎被整合到一个协调的代谢途径中。我们提出存在一些具有广泛特异性、低亲和力的传感受体，而不是为每种诱导化合物都配备数百种受体，这些受体将监测诱导剂的总体水平以触发代谢酶的产生。为支持这一模型，我们分离出一种新型核受体，称为类固醇和外源性物质受体（SXR），它能响应多种天然和合成化合物激活转录。SXR与RXR形成异源二聚体，该异源二聚体可与类固醇诱导的细胞色素P - 450基因中的反应元件结合并诱导其转录，且在表达这些分解代谢酶的组织中表达。这些结果有力地支持了类固醇传感器假说，并表明广泛特异性传感受体可能代表核受体超家族的一个新分支。
