Cytochrome P450 Family 1 and 3 Function in Aquatic Species

细胞色素 P450 家族 1 和 3 在水生物种中的功能

• 批准号: RGPIN-2016-05767
• 负责人: Wilson, Joanna
• 金额: $ 2.55万
• 依托单位: McMaster University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=709993
• 关键词: Cytochrome; P450; Family; Function; Aquatic

Cytochrome P450 enzymes (CYPs) are critical for the production and metabolism of important molecules such as hormones. CYPs are also critical for the metabolism of environmental contaminants. Genes in the CYP1 and CYP3 families mediate both xenobiotic and steroid metabolism. Despite their roles, we are only beginning to understand the regulation and function of CYP genes in aquatic species. Our lab has played an important role in the identification and study of CYPs in fish and aquatic annelids. Newly identified CYP1 and CYP3 family gene sequences in both groups suggest novel metabolic functions. To build on research previously completed in our laboratory, the major objectives of this research are to understand the regulation, expression and function of xenobiotic and steroid metabolizing genes in aquatic species. The hypothesis is that diversity in gene sequences predicts the acquisition of novel metabolic function in aquatic species. Using zebrafish as a model teleost species, we will examine CYP1D1 and CYP3C1-4. Function will be assessed by using expressed proteins in a high through put screening approach developed in our last NSERC Discovery. Work from others (CYP1D1) and in our last Discovery (CYP3C1-4) identified the tissue and developmental expression patterns of these genes and suggested the regulatory pathways that may control gene expression. Using pharmacological tools, we will determine the regulation of CYP1D1 and CYP3C1-4 genes in zebrafish. In our last Discovery, our annotation of CYP genes in the genome of the annelid, Capitella telata, identified several CYP1 and CYP3 related genes, two of which have been implicated in xenobiotic metabolism. This aquatic annelid has the capacity to metabolize vertebrate CYP1 substrates, such as polycyclic aromatic hydrocarbons, which are common environmental contaminants. This ability has been linked to the dominance of Capitella in highly contaminated environments and suggests resistance to toxic chemicals. Our prior studies have identified candidates genes for steroid and xenobiotic metabolism and in this proposal we will assess the capacity of Capitella for these functions. Since CYP1 and CYP3 families play such an important role in both steroid and xenobiotic metabolism, we propose to focus on understanding the regulation and function of novel CYP1 and CYP3 genes in aquatic species. These data will determine if novelty in CYP gene sequences has led to novel metabolic capacity that allows these species to withstand contaminated environments. We can apply this knowledge to understand the capacity of a species for xenobiotic metabolism, to understand the relevance of CYP genes for toxicology, and to understand the evolution of detoxification systems.

细胞色素P450酶对激素等重要分子的产生和代谢起着至关重要的作用。环磷酰胺对环境污染物的新陈代谢也是至关重要的。细胞色素P450 1和细胞色素P3家族的基因调节异源代谢和类固醇代谢。尽管它们发挥了作用，但我们才刚刚开始了解CYP基因在水生物种中的调节和功能。本实验室在鱼类和水生环节动物中的细胞色素P450的鉴定和研究中发挥了重要作用。两组中新发现的细胞色素P450 1和细胞色素P3家族基因序列提示了新的代谢功能。本研究的主要目的是在实验室前期研究的基础上，进一步了解水生生物中外源基因和类固醇代谢基因的调控、表达和功能。这个假说是，基因序列的多样性预测了水生物种获得新的代谢功能。以斑马鱼作为硬骨鱼的模式物种，我们将研究细胞色素P1D1和细胞色素P3C1-4。功能将通过使用我们在NSERC发现的上一次开发的高通量筛选方法中的表达蛋白来进行评估。其他人的工作(CYP1D1)和我们最近的发现(CYP3C1-4)确定了这些基因的组织和发育表达模式，并提出了可能控制基因表达的调控途径。利用药理学工具，我们将确定斑马鱼中CYP1D1和CYP3C1-4基因的调控。在我们最近的发现中，我们对环节动物Capitella Telata基因组中的CyP基因的注释发现了几个与CyP1和CyP3相关的基因，其中两个基因与异源代谢有关。这种水生环节动物具有代谢脊椎动物CYP1底物的能力，如多环芳烃，这些都是常见的环境污染物。这种能力与Capitella在高度污染环境中的优势有关，并表明它对有毒化学物质具有抵抗力。我们之前的研究已经确定了类固醇和异体代谢的候选基因，在这项提议中，我们将评估Capitella对这些功能的能力。鉴于细胞色素P450 1和细胞色素P3家族在类固醇代谢和外来生物代谢中起着重要的作用，我们建议重点了解新的细胞色素P450 1和3基因在水生生物中的调节和功能。这些数据将决定CYP基因序列的新颖性是否导致了新的代谢能力，使这些物种能够抵御污染的环境。我们可以利用这些知识来了解一个物种对异源新陈代谢的能力，了解CYP基因与毒理学的相关性，以及了解解毒系统的进化。