UC San Diego

This research delves into the intricate interplay across absorption, distribution, metabolism, and excretion (ADME) genes such as renal drug transporters to the transcription factors that control their expression, specifically aryl hydrocarbon receptor (AHR), unraveling their profound impact on metabolic processes from organs to organelles. OAT1 and OAT3, renowned drug transporters in the kidney, have established roles in drug and endogenous metabolite transport. However, their unexplored function in regulating dietary natural products (NPs) sparks curiosity. We systematically examined this phenomenon, exploring NPs from Asian (Chinese, Indian Ayurvedic) and Western traditions. Loss of OAT1 and OAT3 function led to alterations in a diverse array of natural products, including flavonoids, B vitamins, indoles, and fatty acids. Through biochemical pathway analysis and in vitro assays, we demonstrated the pivotal role of these transporters in handling non-synthetic small molecule NPs, highlighting their significance in NP-derived antioxidants and nutrients' metabolism.Simultaneously, we delved into AHR's multifaceted roles, revealing its involvement in detoxification, development, immune response, and chronic kidney disease. AHR orchestrates a Remote Sensing and Signaling Network, influencing drug transporters and metabolizing enzymes. Our comprehensive omics analysis in Ahr-/- mice elucidated AHR's regulation of 290 metabolites, impacting vital pathways related to fatty acids, bile acids, gut microbiome products, antioxidants, choline derivatives, and uremic toxins. Chemoinformatics analysis uncovered AHR's role in metabolite hydrophobicity, potentially affecting their tissue movement. Indolepropionate, among AHR ligands, significantly altered and activated AHR in human and murine cells. Integrating transcriptomics and metabolomics data through genome-scale metabolic reconstruction unveiled AHR's influence on organic acids and redox states, underscoring its central role in metabolism and signaling across organs and scales. This thesis provides a comprehensive exploration of renal drug transporters (OAT1 and OAT3) and the regulators involved in controlling expression of these ADME genes, illuminating their significant contributions to metabolic regulation. By bridging the knowledge gaps between these essential components, our research not only enhances our understanding of fundamental biological processes but also opens avenues for targeted interventions, promising advances in therapeutics and personalized medicine.