Zhou Changcheng, Poulton Emma-Jane, Grün Felix, Bammler Theo K, Blumberg Bruce, Thummel Kenneth E, Eaton David L
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA.
Mol Pharmacol. 2007 Jan;71(1):220-9. doi: 10.1124/mol.106.029264. Epub 2006 Oct 6.
Sulforaphane (SFN) is a biologically active phytochemical found abundantly in broccoli. SFN has been promoted as a putative chemopreventive agent to reduce cancer, and most studies have associated its anti-cancer effects with the induction of phase II xenobiotic metabolism enzymes via activation of the Keap1/Nrf2 antioxidant response pathway. Interestingly, SFN can significantly down-regulate cytochrome P450 3A4 (CYP3A4) expression in human primary hepatocytes. CYP3A4 is responsible for the hepatic and intestinal metabolism of numerous protoxicants, pharmaceutical compounds, and endogenous sterols. Among the most important mediators of CYP3A4 expression is the nuclear hormone receptor, steroid and xenobiotic receptor (SXR; also called "hPXR"). SXR functions as a xenobiotic sensor to coordinately regulate xenobiotic metabolism via transcriptional regulation of xenobiotic-detoxifying enzymes and transporters. Here, we report that SFN is a specific antagonist of human SXR and that it inhibits SXR-mediated induction of drug clearance. SFN can bind directly to SXR, inhibit SXR coactivator recruitment, and efficiently repress SXR activities. Furthermore, SFN inhibited SXR-mediated CYP3A4 expression and CYP3A4-catalyzed midazolam clearance in human primary hepatocytes. Thus, SFN is the first identified naturally occurring antagonist for SXR (hPXR). Because induction of CYP3A4 can result in adverse drug responses (e.g., lack of efficacy), which are a major public health problem, this discovery could lead to the development of important new therapeutic and dietary approaches to reduce the frequency of undesirable inducer-drug interactions.
萝卜硫素（SFN）是一种在西兰花中大量存在的具有生物活性的植物化学物质。SFN已被推崇为一种假定的化学预防剂，用于降低癌症风险，并且大多数研究已将其抗癌作用与通过激活Keap1/Nrf2抗氧化反应途径诱导II相异生物质代谢酶联系起来。有趣的是，SFN可显著下调人原代肝细胞中细胞色素P450 3A4（CYP3A4）的表达。CYP3A4负责多种原毒物、药物化合物和内源性固醇的肝脏和肠道代谢。CYP3A4表达的最重要调节因子之一是核激素受体，类固醇和异生物质受体（SXR；也称为“hPXR”）。SXR作为一种异生物质传感器，通过对异生物质解毒酶和转运蛋白的转录调控来协调调节异生物质代谢。在此，我们报告SFN是人类SXR的特异性拮抗剂，并且它抑制SXR介导的药物清除诱导。SFN可直接与SXR结合，抑制SXR共激活剂的募集，并有效抑制SXR活性。此外，SFN在人原代肝细胞中抑制SXR介导的CYP3A4表达和CYP3A4催化的咪达唑仑清除。因此，SFN是首个被鉴定出的天然存在的SXR（hPXR）拮抗剂。由于CYP3A4的诱导可导致不良药物反应（例如，疗效缺乏），这是一个主要的公共卫生问题，这一发现可能会促成重要的新治疗和饮食方法的开发，以减少不良诱导剂 - 药物相互作用的发生频率。
