Regulation and functional significance of the ABC transporter P-glycoprotein (ABCB1) in fish

鱼类 ABC 转运蛋白 P-糖蛋白 (ABCB1) 的调控及其功能意义

• 批准号: RGPIN-2014-04513
• 负责人: Kennedy, Christopher
• 金额: $ 3.57万
• 依托单位: Simon Fraser University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=587853
• 关键词: Regulation; functional; significance; ABC; transporter

Organisms regulate endogenous and xenobiotic chemicals to reduce their accumulation and the potential for toxic effects. The mechanisms for chemical homeostasis include: 1) biotransformation to metabolites , 2) membrane efflux transport of metabolites , and 3) membrane efflux transport of unmetabolized parent compound (e.g. Phase III transport: P-glycoprotein [P-gp, ABCB family]). The transmembrane protein P-gp, is a chemical efflux transporter in the ATP-binding cassette (ABC) transport protein superfamily (ABCB1/MDR1). P-gp provides a multixenobiotic resistance mechanism (MXR) to contaminants in fish that is analogous to the multidrug resistance (MDR) mechanism found in mammals . MXR is a phenomenon of tremendous adaptational value for fish living in polluted environments that acts through an enhanced expression of P-gp which restricts xenobiotic uptake. In fish, P-gp is predominantly expressed in organs that have an excretion (e.g. liver), absorption (e.g. intestine), or barrier (e.g. blood brain barrier [BBB]) function. Although considerable information on P-gp in mammals has been generated in recent years, we still do not know how P-gp works as an efflux pump or what its roles are in physiology, although it is believed to be the only ABC transporter whose sole function is to protect cells against a wide range of chemicals. In mammals, P-gp transports a broad variety of compounds that include endogenous molecules, drugs, and environmental chemicals. In fish, the range of known substrates on which P-gp act is limited and appears to be different from mammals. Defining a common pharmacore for both substrates is necessary to begin to understand P-gp’s role in chemical toxicokinetics. This is particularly important when fish are exposed to both P-gp substrates and inhibitors in chemical mixtures; altered toxicokinetics may lead to increased accumulation of chemicals and the susceptibility to toxic effects. Very little information exists on the constitutive or inducible levels of P-gp following xenobiotic exposure in fish. Equally limited, is information regarding P-gp regulation or the signaling pathways involved in its induction. Limited evidence suggests that controls for the up-regulation of P-gp can occur in response to a number of signals, including specific xenobiotics, endogenous molecules, and stress. A newly emerging field of study concerns the roles of nuclear factors (e.g. Pregnane X receptor [PXR]) on P-gp expression. Common and coordinated signaling mechanisms may exist for xenobiotic metabolizing enzymes through pathways such as PXR. Well-established in vitro fish cell model systems and whole animals will be used to investigate the substrate base, P-gp levels, induction, regulation, and signaling pathways proposed/described above. The ecological and environmental significance of P-gp function at the whole organism level will investigated using the blood brain barrier (BBB) as a model tissue. The BBB is the primary interface between the peripheral circulation and the CNS of vertebrates. The molecular basis of the selective nature of the BBB includes P-gp that prevents some xenobiotics from entering the CNS. Very little information exists regarding the significance of the BBB in fish. The role P-gp plays in its function is an area of teleost physiology that is under researched. This research has several aims: 1) to assess the physiological and toxicological roles of P-gp in teleosts, 2) to elucidate the regulatory mechanisms underlying P-gp expression, 3) to increase knowledge regarding the teleost P-gp substrate base, 4) to determine if a relationship exists between P-gp and other chemical defense systems, and 5) to determine the functional significance of the BBB in fish and P-gp's role in it.

生物体调节内源性和外源性化学品，以减少其积累和潜在的毒性作用。 化学稳态的机制包括：1）生物转化为代谢产物，2）代谢产物的膜外排转运，3）未代谢母体化合物的膜外排转运（例如III期转运：P-糖蛋白[P-gp，ABCB家族]）。 跨膜蛋白P-gp是ATP结合盒（ABC）转运蛋白超家族（ABCB 1/MDR 1）中的一种化学外排转运蛋白。P-gp在鱼类中提供了一种对污染物的多异源性耐药机制（MXR），类似于在哺乳动物中发现的多药耐药（MDR）机制。MXR是一种对生活在污染环境中的鱼类具有巨大适应价值的现象，其通过增强P-gp的表达来发挥作用，P-gp限制异生物质摄取。 在鱼类中，P-gp主要在具有排泄（例如肝脏）、吸收（例如肠）或屏障（例如血脑屏障[BBB]）功能的器官中表达。 尽管近年来已经产生了大量关于哺乳动物中P-gp的信息，但我们仍然不知道P-gp如何作为外排泵工作或其在生理学中的作用，尽管它被认为是唯一的ABC转运蛋白，其唯一功能是保护细胞免受各种化学物质的侵害。 在哺乳动物中，P-gp转运多种化合物，包括内源性分子、药物和环境化学物质。在鱼类中，P-gp作用的已知底物的范围是有限的，并且似乎与哺乳动物不同。为两种底物定义一个共同的药效中心对于开始理解P-gp在化学毒物代谢中的作用是必要的。 这是特别重要的，当鱼暴露于P-gp底物和化学混合物中的抑制剂;改变toxicokerase可能会导致化学品的积累增加和对毒性作用的敏感性。 非常少的信息存在的组成或诱导水平的P-gp以下外源性暴露在鱼。 同样有限的，是关于P-gp调节或参与其诱导的信号通路的信息。有限的证据表明，控制P-gp的上调可以发生在响应于一些信号，包括特定的外源性物质，内源性分子和压力。一个新兴的研究领域涉及核因子（例如孕烷X受体[PXR]）对P-gp表达的作用。通过PXR等途径，异生素代谢酶可能存在共同和协调的信号传导机制。 将使用完善的体外鱼细胞模型系统和整个动物来研究上述提出/描述的底物基础、P-gp水平、诱导、调节和信号传导途径。以血脑屏障（BBB）为模型组织，研究P-gp功能在整个生物体水平上的生态和环境意义。血脑屏障是脊椎动物外周循环和中枢神经系统之间的主要界面。血脑屏障选择性的分子基础包括P-gp，其阻止某些外源性物质进入CNS。关于BBB在鱼类中的重要性的信息很少。P-gp在其功能中的作用是硬骨鱼生理学的一个研究领域。 这项研究有几个目标：1）评估P-gp在硬骨鱼中的生理和毒理学作用，2）阐明P-gp表达的调节机制，3）增加关于硬骨鱼P-gp底物基础的知识，4）确定P-gp与其他化学防御系统之间是否存在关系，（5）探讨鱼类血脑屏障的功能意义及P-gp在血脑屏障中的作用。