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

项目总结 研究表明，多达80%的癌症患者报告使用了植物性膳食补充剂(BDS) 在他们最初被诊断出癌症之后。研究发现，癌症患者摄入的BDS比 否则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 生活质量。根据对美国食品和药物管理局不良事件报告系统的审查 数据库中，我们的研究小组发现，在非相互作用的抗癌药物之间存在潜在的风险 和含有Eurpe Polacea Mart的BDS。(Açaí)，其中包括心血管不良风险的增加 当事件放在一起时。然而，这种相互作用的机制仍不清楚。的受欢迎程度 含有阿萨伊的产品继续增长，现在是2022年，阿萨伊是世界上最常用的40种植物药之一。 美国。基于对文献的交叉检查，我们假设肝脏UDP- 葡萄糖醛酸基转移酶(UGT)是阿萨伊化合物抑制可促进 与抗癌药物一起服用时的心血管不良事件。这项提案将确定阿萨伊的提取物 包含UGT抑制剂并测试我们新的自动化全球天然产品社会分子网络 (GNP)与生物活性工具相结合，用于阐明抑制化合物。具体目标1A：生成UGT 抑制试验是为了阐明阿萨伊提取物中的化学成分对UGT酶的抑制作用。 将测试提取物对UGT亚型1A1、1A3、1A4、1A6、1A9和2B7的抑制作用 从杆状病毒转基因的昆虫细胞中产生人UGT。特定目标1B：LC-MS/MS化学 阿萨伊提取物的指纹将用于形成生物活性分子网络(BMN)，使用我们的自动化 GNP-生物活性仪表板预测UGT的抑制剂。从预测的商业上可以获得的化合物 此工具将在单独测试UGT抑制之前购买和验证。这个项目的结果将是 是含有Açaí的BDS成分产生BDS-抗癌药物的潜在机制 临床上与癌症治疗相关的相互作用。

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.