MITOCHONDRIAL TRANSPORTER ABCB6 IN DRUG METABOLISM AND DISPOSITION IN LIVER

线粒体转运蛋白 ABCB6 在药物代谢和肝脏中的分布

• 批准号: 7959508
• 负责人: Parthasarathy Krishnamurthy
• 金额: $ 19.67万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959508
• 关键词: ABCB6 gene; ATP-Binding Cassette Transporters; Accounting; Acute Intermittent Porphyria; Apoproteins; Cell physiology; Computer Retrieval of Information on Scientific Projects Database; Cytochrome P450; Disease; Drug Interactions; Drug toxicity; Enzyme Inhibition; Funding; Grant; Health; Heme; Hemeproteins; Hepatic; Homeostasis; Institution; Knowledge; Lead Poisoning; Liver; Metabolism; Mitochondria; Modification; Nuclear Receptors; Pharmaceutical Preparations; Play; Protein Isoforms; Research; Research Personnel; Resources; Respiratory Chain; Role; Source; Toxic Environmental Substances; Tryptophanase; United States National Institutes of Health; base; catalase; cytochrome c oxidase; drug biological activity; drug clearance; drug metabolism; enzyme substrate; heme a; interest; overexpression; porphyrin biosynthesis

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Heme plays an important role in many cellular processes and dysregulation of its synthesis contributes to multiple diseases. Cellular heme homeostasis is regulated by multiple mechanisms that have typically been attributed to a combination of synthesis and degradation. Our recent findings extend this paradigm to reveal that a mitochondrial ABC transporter, Abcb6, regulates heme/porphyrin biosynthesis. A large proportion of heme usage in the liver is accounted for by cytochrome P450 isoforms, many of which are associated with drug metabolism. Each P450 is composed of a heme and an apoprotein moiety, whose cellular synthesis are tightly coordinated. Similar tight coordination of synthesis is also observed with other hemoproteins such as cytochrome c oxidase subunits of the mitochondrial respiratory chain, catalase and liver tryptophan 2,3-dioxygenase (TDO). In most of these cases, heme has been established as a transcriptional and translational activator of these hemoproteins. The modification of the enzymatic activity of the cytochrome P450 (CYP) enzymes by inhibition, induction, or activation is of great interest due to the potential of these alterations to greatly change the metabolism of the drug substrate for that enzyme and thereby alter the biological activity of the drug leading to the potential for harmful drug-drug interactions. Indeed P450 activity is impaired in several disorders of heme synthesis, such as in acute porphyrias and in acquired heme synthesis, such as in lead poisoning. Based on these observations we hypothesize that overexpression or interference with Abcb6 function might regulate hepatic CYP450 expression and/or function. Knowledge regarding the impact of Abcb6 on CYP450 activity has both immediate implications on the metabolism and disposition of pharmacological agents and environmental toxins and long term implications on drug clearance and drug toxicity.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 血红素在许多细胞过程中发挥着重要作用，其合成失调会导致多种疾病。细胞血红素稳态由多种机制调节，这些机制通常归因于合成和降解的组合。我们最近的研究结果扩展了这一范式，揭示了线粒体 ABC 转运蛋白 Abcb6 调节血红素/卟啉生物合成。肝脏中血红素使用的很大一部分是由细胞色素 P450 同工型引起的，其中许多同工型与药物代谢有关。每个 P450 由血红素和脱辅基蛋白部分组成，其细胞合成紧密协调。其他血红蛋白也观察到类似的紧密合成协调，例如线粒体呼吸链的细胞色素 c 氧化酶亚基、过氧化氢酶和肝脏色氨酸 2,3-双加氧酶 (TDO)。在大多数情况下，血红素已被确定为这些血红素蛋白的转录和翻译激活剂。通过抑制、诱导或激活来改变细胞色素 P450 (CYP) 酶的酶活性引起了人们极大的兴趣，因为这些改变可能会极大地改变该酶的药物底物的代谢，从而改变其生物活性药物的使用可能会导致有害的药物相互作用。事实上，P450 活性在几种血红素合成疾病中受损，例如急性卟啉症和获得性血红素合成，例如铅中毒。基于这些观察，我们假设过度表达或干扰 Abcb6 功能可能会调节肝 CYP450 表达和/或功能。关于 Abcb6 对 CYP450 活性的影响的知识不仅对药物和环境毒素的代谢和处置有直接影响，而且对药物清除和药物毒性有长期影响。