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.

项目摘要研究表明，多达80％的癌症患者使用植物饮食补充剂（BDS）报告在最初的癌症诊断之后。已经发现BD被癌症患者食用比否则，健康疗法药物的副作用和/或增加的患者可以减轻癌症的副作用生活质量。在检查美国食品和药物管理局不良事件报告系统后数据库，我们的研究小组发现CYP3A4非相互作用抗癌药物之间的潜在风险和包含Euterpe oleracea mart的BDS。（açaí），其中包括增加心血管逆境风险一起进行的事件。但是，这种相互作用的机制仍然未知。受欢迎程度分析产品的分析继续增长，现在在2022年，分析是使用美国。基于文献的盘问，我们假设肝UDP- 谷氨酸转移酶（UGTS）是açaí化合物抑制可以促进的靶标当用抗癌药物服用时心血管不良事件。该建议将确定Açaí的提取物包含UGT抑制剂并测试我们新自动化的全球自然产品社会分子网络（GNP）与生物活性工具耦合，以阐明抑制性化合物。特定目标1A：产生UGT 抑制作用断言，以阐明Açaí提取物中化学构成的潜力，以抑制UGT酶。提取物将测试使用重组的UGT同工型1A1、1A3、1A4、1A6、1A9和2B7测试由杆状病毒转染的昆虫细胞产生的人类UGT。特定目标1B：LC-MS/MS化学 Açaí提取物的指纹将使用我们的自动化来形成生物活性分子网络（BMN） GNPS生物活性仪表板可预测UGT的抑制剂。从该工具将在隔离测试之前购买和验证UGT抑制作用。这个项目的结果将成为构成包含Açaí的BDS的潜在机制，正在引起BDS-Amentancer药物与癌症治疗相关的相互作用。