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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：
9324951
负责人：
Klarissa D Jackson
金额：
$ 13.18万
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/9324951
关键词：
Address Adult African American Alleles Antineoplastic Agents Area Asians Baculoviridae Baculoviruses Biochemical Breast Cancer Treatment CYP3A4 gene CYP3A5 gene Cancer Etiology Caucasians Cellular Stress Cessation of life Clinical Cytochrome P450 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 Activation Metabolic Biotransformation Metabolism Metastatic breast cancer Microsomes Molecular Molecular Toxicology N hydroxylation Oral Pathway interactions Patient risk Patients Pharmaceutical Preparations Preparation Professional Competence Proteins Reaction Recombinants Research Research Design Research Project Grants Risk Risk Factors Role Route Scientist Small Intestines Techniques Testing Time Toxic effect Training Tyrosine Kinase Inhibitor Universities Woman adduct cancer therapy career career development clinically relevant cytotoxicity defined contribution genetic variant improved in vitro Model inhibitor/antagonist insight lapatinib liver injury malignant breast neoplasm metabolic profile oxidation patient population patient safety public health relevance skills targeted treatment tool training opportunity

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）：本研究职业发展计划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在了解临床相关抗癌药物的分子毒理学方面做出重大贡献，以提高其在患者中的安全使用。酪氨酸激酶抑制剂引起的药物性肝损伤是肿瘤治疗中日益突出的临床问题。拉帕替尼是一种双酪氨酸激酶抑制剂，是一种用于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，形成反应性喹奈亚胺，这是一种潜在的毒性代谢物。我的主要假设是CYP3A5的多态性表达导致了拉帕替尼反应性代谢物产生的个体间差异，这可能是肝毒性发展的一个危险因素。本项目的总体目标是明确CYP3A5对拉帕替尼体外代谢和生物活化的贡献，并评估CYP3A5基因变异对拉帕替尼反应性代谢物产生的影响。为了解决这一假设，我们提出了以下具体目标：1)确定CYP3A5在拉帕替尼整体代谢和生物活化中的作用；2)评价CYP3A5基因多态性对拉帕替尼代谢谱的影响；3)检测拉帕替尼在基因型人肝细胞培养中的代谢和细胞毒性。这些体外研究将使用重组P450酶、个体基因型人肝微粒体制剂和使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多态性在拉帕替尼对特殊患者群体的肝毒性潜力中的作用，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的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相关的未解之谜。拟议的研究职业发展计划包括与利普斯科姆大学和范德比尔特大学的导师进行跨机构指导，以使我能够充分利用每位导师提供的杰出优势。这个职业发展计划的关键要素包括与我的指导委员会的定期互动，参加与我的研究相关的研讨会，以及参加职业技能培训的机会。