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

基本信息

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
项目类别：
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

项目摘要

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）：这项研究职业发展建议的总体目标是促进我的发展成为一名独立的研究科学家。我的长期职业目标是为理解临床相关的抗癌药的分子毒理学做出重大贡献，以改善其在患者中的安全使用。与酪氨酸激酶抑制剂相关的药物诱导的肝损伤是癌症治疗中日益增长的临床问题。拉帕替尼是一种双酪氨酸激酶抑制剂，是晚期或转移性乳腺癌治疗师的靶向疗法。但是，与拉帕替尼有关的特质肝毒性可能会限制其在某些患者人群中的使用。这种毒性的机制尚不清楚。 Lapatinib可以通过细胞色素P450（CYP）3A4/5进行代谢激活，形成反应性的奎诺米宁，可能是有毒的代谢产物。我的中心假设是，CYP3A5的多态性表达有助于Lapatinib反应性代谢产物产生的个体间差异，这可能是肝毒性发展的危险因素。该项目的总体目的是定义CYP3A5对Lapatinib体外代谢和生物活化的贡献，并评估CYP3A5遗传变异对Lapatinib反应性代谢产物产生的影响。为了解决该假设，提出了以下具体目的：1）确定CYP3A5在Lapatinib的总代谢和生物活化中的作用； 2）评估CYP3A5遗传多态性对拉帕替尼代谢谱的影响； 3）检查基因分型人肝细胞培养物中拉帕替尼的代谢和细胞毒性。这些体外研究将使用重组P450酶，单个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。该项目将通过深入了解CYP3A5多态性在特殊患者人群中Lapatinib的肝毒性潜力中的作用来推进该领域。为了进一步发展我的研究技能，我将在研究设计方面的额外培训中受益于利用生化技术，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的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有关的未解决问题。拟议的研究职业发展计划涉及与Lipscomb大学和范德比尔特大学的导师跨机构指导，以使我能够利用每个导师提供的杰出优势。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，与我的研究相关的研讨会以及从事职业技能培训的机会。