Virus-Receptor Interaction and CYP3A Expression

病毒-受体相互作用和 CYP3A 表达

• 批准号: 6866479
• 负责人: Maria A Croyle
• 金额: $ 10.8万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-05 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6866479
• 关键词: Adenoviridae; antibody neutralization test; cytochrome P450; cytokine; drug metabolism; gene expression; genetic transcription; host organism interaction; immunocytochemistry; integrins; laboratory rat; liver cells; liver metabolism; posttranscriptional RNA processing; posttranslational modifications; protein protein interaction; receptor binding; virus infection mechanism; virus protein; virus receptors; western blottings

DESCRIPTION (provided by applicant): During infection and inflammation, the capacity of the liver to metabolize drugs is impaired due to a reduction in hepatic content of cytochrome P450 (CYP), which can render clinically important medications ineffective or toxic. Cytokines and chemokines contribute as blood borne mediators of this effect on the liver. However, the exact mechanism by which cytokines alter CYP is unknown. Upon infection, viruses take over cellular machinery for self-replication and survival from the time the virus binds to receptors on the cell surface. Integrins, heterodimeric proteins expressed on all nucleated cells, serve as a site of entry for various pathogens. They also initiate signals inside the cell to regulate gene transcription, cell proliferation and survival. Studies of CYP expression in primary cultures of rat and human hepatocytes suggest that integrins influence CYP expression and function. The objective of this study is to investigate mechanisms of long-term virus-induced alterations in drug metabolism, using recombinant adenoviral vectors as prototype pathogens. The hypothesis being tested is that interaction of viral proteins with integrin receptors is responsible for changes of hepatic CYP gene expression and function. Capsid protein effects will be assessed by treating rats with either a "gutted" virus with all viral genes deleted, PEGylated virus which does not interact with integrin receptors, UV inactivated or wild type virus. We will also determine if changes in CYP by these agents is achieved by transcriptional, posttranscriptiontional or postranslational mechanisms in vivo and in macrophage free primary cultures of rat hepatocytes to rule out cytokine effects. This hypothesis has not been tested and could have significant impact on current thought on regulation of CYP gene expression. This is of vast importance as cases of viral infection escalate in the general population and viruses are used as medicinal agents for gene therapy and vaccination protocols. Results from these studies could lead to the development of new anti-viral agents, identification of genetic markers to screen patients for potential aberrations in drug metabolism, and possibly to methods to mitigate drug-induced toxicity during viral infection and design of safer retargeted viruses for therapeutic applications.

描述（由申请方提供）：在感染和炎症期间，由于肝细胞色素P450（CYP）含量减少，肝脏代谢药物的能力受损，这可能导致临床重要药物无效或有毒。细胞因子和趋化因子作为这种对肝脏作用的血液传播介质。然而，细胞因子改变细胞增殖的确切机制尚不清楚。一旦感染，病毒从病毒与细胞表面上的受体结合时起接管细胞机器进行自我复制和存活。整合素，异源二聚体蛋白质表达的所有有核细胞，作为一个网站的各种病原体的进入。它们还启动细胞内的信号以调节基因转录、细胞增殖和存活。在大鼠和人肝细胞原代培养物中的cDNA 3表达的研究表明，整合素影响cDNA 3的表达和功能。本研究的目的是探讨长期病毒诱导的药物代谢改变的机制，使用重组腺病毒载体作为原型病原体。正在测试的假设是，病毒蛋白与整合素受体的相互作用是导致肝纤维化基因表达和功能变化的原因。将通过用所有病毒基因缺失的“去内脏”病毒、不与整联蛋白受体相互作用的聚乙二醇化病毒、UV灭活或野生型病毒处理大鼠来评估衣壳蛋白效应。我们还将确定这些药物引起的细胞因子变化是否是通过体内转录、转录后或翻译后机制以及在大鼠肝细胞的无巨噬细胞原代培养物中实现的，以排除细胞因子效应。这一假设尚未得到验证，可能对目前关于调节β-内酰胺酶基因表达的思想产生重大影响。这是非常重要的，因为病毒感染病例在一般人群中不断增加，病毒被用作基因治疗和疫苗接种方案的药物。这些研究的结果可能导致开发新的抗病毒药物，鉴定遗传标记以筛选患者药物代谢中的潜在畸变，并可能导致在病毒感染期间减轻药物诱导的毒性的方法，以及设计更安全的重靶向病毒用于治疗应用。

项目成果

Influence of method of systemic administration of adenovirus on virus-mediated toxicity: focus on mortality, virus distribution, and drug metabolism.

• DOI: 10.1016/j.vascn.2008.07.003
• 发表时间: 2008-11
• 期刊: Journal of pharmacological and toxicological methods
• 影响因子: 1.9
• 作者: Boquet MP;Wonganan P;Dekker JD;Croyle MA
• 通讯作者: Croyle MA

Drug-virus interaction: effect of administration of recombinant adenoviruses on the pharmacokinetics of docetaxel in a rat model.

• DOI: 10.1038/cgt.2008.99
• 发表时间: 2009-05
• 期刊: Cancer gene therapy
• 影响因子: 6.4

Integrin Receptors Play a Key Role in the Regulation of Hepatic CYP3A.

整合素受体在肝脏 CYP3A 的调节中发挥关键作用。

• DOI: 10.1124/dmd.115.068874
• 发表时间: 2016
• 期刊: Drug metabolism and disposition: the biological fate of chemicals
• 作者: Jonsson-Schmunk,Kristina;Wonganan,Piynauch;Choi,JinHuk;Callahan,ShellieM;Croyle,MariaA
• 通讯作者: Croyle,MariaA