Bile acid detoxification by nuclear receptor-mediated CYP3A regulation

通过核受体介导的 CYP3A 调节进行胆汁酸解毒

• 批准号: nhmrc : 153890
• 负责人: Prof Christopher Liddle
• 金额: $ 13.1万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2001
• 资助国家: 澳大利亚
• 起止时间: 2001-01-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/bile-acid-detoxification-cyp3a-regulation/100562
• 关键词: Bile; acid; detoxification; nuclear; receptor

Liver diseases in which there is obstruction to bile flow (cholestatic liver diseases) can lead to liver failure, liver cirrhosis as well as a diminished quality of life. Patients suffer from severe itching which may prove difficult to control. It is thought that many of these adverse effects of obstructed bile flow are due to the retention of a component of bile, called bile acids, within the body. Bile acids are detergent-like compounds formed from cholesterol. Some bile acids are highly toxic and cause the death of cells in the liver if their concentration becomes too high. Evidence has emerged that the body has control mechanisms to try and combat rising levels of bile acids in cholestatic liver diseases. One such mechanism, which is the subject of this application, is the metabolism of bile acids to less toxic forms, by a process called hydroxylation. A particular class of liver enzymes, known as cytochromes P450 CYP3As, appear to mediate these hydroxylation reactions. Liver cytochrome P450 enzymes are important to medicine in areas as broad as drug breakdown, steroid hormone regulation and the formation or elimination of cancer causing chemicals. These enzymes are present in high concentration in the human liver, but the factors governing how much of these enzymes are produced have been poorly understood. The present projects builds on discoveries concerning the regulation of cytochrome P450 enzymes made by our group over the last few years, including an in-depth understanding of the way the production of CYP3As are increased by some drugs. We intend to determine the mechanism by which bile acids increase the level of CYP3A enzymes are how effective these enzymes are in hydroxylating bile acids. An understanding of these issues will allow us to better manage patents with cholestatic liver diseases and develop new strategies for treating these diseases, for example, development of novel drugs that increase bile acid hydroxylation in the liver.

胆汁流动受阻的肝脏疾病（胆汁淤积性肝病）可导致肝衰竭、肝硬化以及生活质量下降。患者患有严重的瘙痒，这可能证明难以控制。据认为，胆汁流动受阻的许多不利影响是由于胆汁的一种成分（称为胆汁酸）在体内的滞留。胆汁酸是由胆固醇形成的洗涤剂样化合物。一些胆汁酸是高毒性的，如果它们的浓度过高，会导致肝细胞死亡。有证据表明，在胆汁淤积性肝病中，身体有控制机制来试图对抗胆汁酸水平的上升。作为本申请主题的一种这样的机制是通过称为羟基化的过程将胆汁酸代谢成毒性较小的形式。一类特殊的肝酶，称为细胞色素P450 CYP3A，似乎介导这些羟基化反应。肝细胞色素P450酶在药物分解、类固醇激素调节和致癌化学物质的形成或消除等广泛领域对医学很重要。这些酶在人类肝脏中以高浓度存在，但对这些酶产生多少的控制因素知之甚少。目前的项目建立在我们小组过去几年中关于细胞色素P450酶调节的发现的基础上，包括对某些药物增加CYP3A产量的方式的深入了解。我们打算确定胆汁酸增加CYP3A酶水平的机制是这些酶在羟基化胆汁酸中的有效性。了解这些问题将使我们能够更好地管理胆汁淤积性肝病患者，并开发治疗这些疾病的新策略，例如，开发增加肝脏中胆汁酸羟基化的新药。