Evaluation of Euterpe oleracea Mart. (açaí) for inhibition of UGTs as a mechanism of botanical-drug interactions involving anticancer drugs

对Euterpe oleracea Mart 的评价。

基本信息

批准号：
10595328
负责人：
Kabre Heck
金额：
$ 3.86万
依托单位：
AUBURN UNIVERSITY AT AUBURN
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-03 至 2024-10-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10595328
关键词：
Adverse event Antineoplastic Agents Baculoviruses Biological Biological Assay Blood Vessels Botanical dietary supplements Botanicals CYP3A4 gene Cancer Patient Cardiotoxicity Cardiovascular system Cause of Death Cells Cessation of life Chemicals Collaborations Complement Complex Consumption Coupled Data Data Set Database Management Systems Development Drug Interactions Drug Prescriptions Educational process of instructing Enzyme Kinetics Enzymes Ethanol Euterpe Evaluation Excretory function Experimental Designs Faculty Fruit Glucosides Glucuronosyltransferase Health Hepatic Human In Vitro Insecta Institution Kidney Knowledge Laboratories Letters Life Literature Liver Malignant Neoplasms Mass Spectrum Analysis Mentorship Metabolic Biotransformation Metabolism Methanol Molecular National Center for Complementary and Integrative Health Natural Products Outcome Patients Pharmaceutical Preparations Phase Principal Investigator Probability Protein Isoforms Quality of life Recombinants Reporting Research Research Personnel Resolution Review Literature Risk Source Standardization Substrate Specificity Techniques Testing Time Toxic effect Training Transfection Translations United States United States Food and Drug Administration United States National Institutes of Health Validation Water Work assay development bioactive natural products cancer diagnosis cancer therapy cardiovascular risk factor career chemical fingerprinting chemotherapeutic agent chemotherapy clinically relevant dashboard experience experimental study hydrophilicity inhibitor lipophilicity member predictive tools programs protective effect seal side effect skills social tool

项目摘要

PROJECT SUMMARY Studies have shown that up to 80% of cancer patients reported using botanical dietary supplements (BDS) following their initial cancer diagnoses. BDS have been found to be consumed more by cancer patients than otherwise healthier patients without cancer to alleviate side effects of chemotherapy drugs and/or increase quality of life. Upon examination of the U.S. Food and Drug Administration Adverse Event Reporting System database, our research team found an indicated potential risk between CYP3A4 non-interactive anticancer drugs and BDS containing Euterpe oleracea Mart. (açaí), which included an increased risk for cardiovascular adverse events when taken together. However, the mechanism of this interaction remains unknown. The popularity of açaí containing products continues to grow and, now in 2022, açaí is among the top 40 botanicals used in the United States. Based on a cross-examination of the literature, we hypothesize that hepatic UDP- glucuronosyltransferases (UGTs) are the target in which inhibition by compounds in açaí could promote cardiovascular adverse events when taken with anticancer drugs. This proposal will identify extracts of açaí containing UGT inhibitors and test our newly automated Global Natural Product Social Molecular Networking (GNPS) coupled to Bioactivity tool for elucidation of inhibitory compounds. Specific Aim 1A: Generate UGT inhibition assays to elucidate the potential for chemical constituents in açaí extract for inhibition of UGT enzymes. Extracts will be tested for inhibition of UGT isoforms 1A1, 1A3, 1A4, 1A6, 1A9, and 2B7 using recombinant human UGTs generated from baculovirus-transfected insect cells. Specific Aim 1B: LC-MS/MS chemical fingerprints of açaí extracts will be used to form Bioactive Molecular Networks (BMN) using our automated GNPS-Bioactivity dashboard to predict inhibitors of UGTs. Commercially available compounds predicted from this tool will be purchased and verified before testing in isolation for UGT inhibition. The result of this project will be a potential mechanism by which constituents of BDS containing açaí are causing BDS-anticancer drug interactions that are clinically relevant for the treatment of cancer.

项目概要研究表明，高达 80% 的癌症患者报告使用植物膳食补充剂 (BDS) 研究发现，癌症患者在初次诊断出癌症后消耗的 BDS 量要多于癌症患者。原本更健康的非癌症患者可以减轻化疗药物的副作用和/或增加经美国食品和药物管理局不良事件报告系统检查。数据库中，我们的研究团队发现 CYP3A4 非相互作用抗癌药物之间存在潜在风险和含有 Euterpe oleracea Mart (açaí) 的 BDS，其中心血管不良风险增加。然而，这种相互作用的机制仍然未知。含有巴西莓果的产品持续增长，到 2022 年，巴西莓果已跻身于食品加工中使用的 40 种顶级植物药之列。根据对文献的交叉检查，我们欺负了肝脏 UDP- 葡萄糖醛酸基转移酶 (UGT) 是巴西莓中化合物的抑制作用的靶标，可促进与抗癌药物一起服用时的心血管不良事件该提案将鉴定巴西莓提取物。含有 UGT 抑制剂并测试我们新近自动化的全球天然产物社交分子网络 (GNPS) 与生物活性工具结合用于阐明抑制性化合物具体目标 1A：生成 UGT。抑制试验阐明巴西莓提取物中化学成分抑制 UGT 酶的潜力。将使用重组酶测试提取物对 UGT 同工型 1A1、1A3、1A4、1A6、1A9 和 2B7 的抑制作用由杆状病毒转染的昆虫细胞产生的人类 UGT。具体目标 1B：LC-MS/MS 化学物质。巴西莓提取物的指纹将用于使用我们的自动化技术形成生物活性分子网络 (BMN) GNPS-生物活性仪表板用于预测 UGT 抑制剂。该工具将在单独测试 UGT 抑制之前购买并验证。该项目的结果将。是含有巴西莓的 BDS 成分引发 BDS 抗癌药物的潜在机制与癌症治疗临床相关的相互作用。