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.