Role of Cytochrome P450 3A5 in the Metabolism and Hepatotoxicity of Lapatinib

细胞色素 P450 3A5 在拉帕替尼代谢和肝毒性中的作用

• 批准号: 8805458
• 负责人: Klarissa D Jackson
• 金额: $ 13.11万
• 依托单位: LIPSCOMB UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-17 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8805458
• 关键词: Address; Adult; African; Alleles; Antineoplastic Agents; Area; Asians; Baculoviruses; Biochemical; Breast; Breast Cancer Treatment; CYP3A4 gene; CYP3A5 gene; Cancer Etiology; Caucasians; Caucasoid Race; Cellular Stress; Cessation of life; Clinical; Critiques; Cytochrome P450; Cytochrome P450 3A4; Dealkylation; Development; Development Plans; Drug toxicity; ERBB2 gene; Elements; Enzymes; Ethnic group; Fostering; Frequencies; Generations; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Glutathione; Goals; Hepatic; Hepatocyte; Hepatotoxicity; Human; In Vitro; Incidence; Individual; Individual Differences; Investigation; Kinetics; Knowledge; Lead; Life; Liver; Mediating; Mentors; Mentorship; Metabolic; Metabolic Activation; Metabolic Biotransformation; Metabolism; Microsomes; Molecular; Molecular Toxicology; Pathway interactions; Patients; Pharmaceutical Preparations; Preparation; Proteins; Reaction; Recombinants; Relative (related person); Research; Research Design; Research Project Grants; Risk; Risk Factors; Role; Route; Scientist; Small Intestines; Techniques; Testing; Time; Toxic effect; Training; Tyrosine Kinase Inhibitor; Universities; Variant; Woman; Work; Writing; adduct; cancer therapy; career; career development; clinically relevant; cytotoxicity; defined contribution; improved; in vitro Model; inhibitor/antagonist; insight; lapatinib; liver injury; malignant breast neoplasm; meetings; oxidation; patient population; patient safety; public health relevance; skills; tool

DESCRIPTION (provided by applicant): The overall goal of this research career development proposal is to foster my development to becoming an independent research scientist. My long-term career goal is to make significant contributions towards understanding the molecular toxicology of clinically relevant anti-cancer agents to improve their safe use in patients. Drug-induced liver injury associated with tyrosine kinase inhibitors is a growing clinical problem in cancer therapy. Lapatinib, a dual tyrosine kinase inhibitor, is a targeted therapy for the treatmen of advanced or metastatic breast cancer. However, idiosyncratic hepatotoxicity associated with lapatinib may limit its use in certain patient populations. The mechanism(s) of this toxicity are unknown. Lapatinib can undergo metabolic activation by cytochrome P450 (CYP) 3A4/5 to form a reactive quinoneimine, potentially toxic metabolite. My central hypothesis is that polymorphic expression of CYP3A5 contributes to inter-individual differences in the generation of reactive metabolites of lapatinib, which may be a risk factor for the development of hepatotoxicity. The overall goal of this project is to define the contribution of CYP3A5 to the metabolism and bioactivation of lapatinib in vitro, and evaluate the impact of CYP3A5 genetic variation on the generation of reactive metabolites of lapatinib. To address the hypothesis, the following specific aims are proposed: 1) Determine the role of CYP3A5 in the overall metabolism and bioactivation of lapatinib; 2) Evaluate the effect of CYP3A5 genetic polymorphisms on the metabolic profile of lapatinib; and 3) Examine the metabolism and cytotoxicity of lapatinib in genotyped human hepatocyte cultures. These in vitro investigations will be carried out using recombinant P450 enzymes, individual genotyped human liver microsomal preparations, and primary human hepatocytes utilizing enzyme selective inhibitors. This project will advance the field by providing insight into the role of CYP3A5 polymorphism in the hepatotoxic potential of lapatinib in special patient populations. To further develop my research skills, I will benefit fro additional training in research design focused on utilizing biochemical techniques, in vitro models, and analytical approaches to characterize drug biotransformation and identify potential toxicity pathways. Gaining more knowledge and new skills in these areas will help improve my ability to develop high quality research projects to address unanswered questions in related to cancer treatment and drug toxicity. The proposed research career development plan involves cross-institutional mentorship with mentors at Lipscomb University and Vanderbilt University to allow me to capitalize on the outstanding strengths that each mentor offers. Key elements of this career development plan include regular interactions with my mentoring committee, participation in seminars relevant to my research, and engaging in opportunities for training in career skills.

描述（由申请人提供）：该研究职业发展提案的总体目标是促进我成为一名独立的研究科学家。我的长期职业目标是为了解临床相关抗癌药物的分子毒理学做出重大贡献，以提高其在患者中的安全使用。与酪氨酸激酶抑制剂相关的药物引起的肝损伤是癌症治疗中日益严重的临床问题。拉帕替尼是一种双重酪氨酸激酶抑制剂，是治疗晚期或转移性乳腺癌的靶向疗法。然而，与拉帕替尼相关的特殊肝毒性可能限制其在某些患者群体中的使用。这种毒性的机制尚不清楚。拉帕替尼可以通过细胞色素 P450 (CYP) 3A4/5 进行代谢激活，形成反应性醌亚胺，具有潜在毒性的代谢物。我的中心假设是，CYP3A5 的多态性表达导致拉帕替尼反应性代谢产物产生的个体间差异，这可能是发生肝毒性的危险因素。该项目的总体目标是明确CYP3A5对拉帕替尼体外代谢和生物激活的贡献，并评估CYP3A5遗传变异对拉帕替尼反应性代谢产物产生的影响。为了解决这一假设，提出以下具体目标：1）确定CYP3A5在拉帕替尼整体代谢和生物激活中的作用； 2）评估CYP3A5基因多态性对拉帕替尼代谢谱的影响； 3) 检查拉帕替尼在基因型人类肝细胞培养物中的代谢和细胞毒性。这些体外研究将使用重组 P450 酶、个体基因分型的人肝微粒体制剂以及利用酶选择性抑制剂的原代人肝细胞进行。该项目将深入了解 CYP3A5 多态性在拉帕替尼对特殊患者群体的肝毒性潜力中的作用，从而推动该领域的发展。为了进一步发展我的研究技能，我将受益于研究设计方面的额外培训，重点是利用生化技术、体外模型和分析方法来表征药物生物转化并确定潜在的毒性途径。在这些领域获得更多知识和新技能将有助于提高我开发高质量研究项目的能力，以解决与癌症治疗和药物毒性相关的悬而未决的问题。拟议的研究职业发展计划涉及利普斯科姆大学和范德比尔特大学导师的跨机构指导，使我能够利用每位导师所提供的突出优势。该职业发展计划的关键要素包括与我的指导委员会定期互动、参加与我的研究相关的研讨会以及参与职业技能培训的机会。