Impact of Sex Chromosomes and Hormones on Drug Metabolism and Transport

About This Grant

Project Summary (overview of research in the laboratory, the goals for the next five years, and an overall vision of the research program) Standard drug treatments often fail to produce the optimal therapeutic effects or, in certain instances, cause severe toxicity. Understanding interindividual variability in drug responses is crucial for optimizing pharmacotherapy. Our lab utilizes pharmacokinetics and pharmaco-omics approaches, including pharmacogenomics, proteomics, and metabolomics, to identify genetic and non-genetic factors influencing drug disposition and response. Through biomarker discovery, mechanistic exploration and predictive modeling, our research aims to advance precision medicine, optimizing drug efficacy and safety. Sex-based differences is a key factor contributing to the variability in drug response, with women experiencing nearly twice the rate of adverse drug reactions as men, and fatal drug overdoses among women have risen significantly. These disparities are largely driven by sex differences in drug-metabolizing enzymes and transporters (DMETs). However, the regulation of DMETs by sex chromosomes and hormones remains poorly understood, contributing to the sex-biased treatment failure and increased toxicity risk. Over the next five years, we aim to address three critical knowledge gaps: (1) the roles of sex chromosomes and hormones in DMET regulation are not well-defined, (2) the impact of hormonal fluctuations, particularly around menopause, on DMET expression and function is poorly characterized, and (3) the full extent of sex-based differences in human DMET expression and activity remains unclear. To tackle these challenges, we will integrate pharmaco-omics tools, innovative animal models, and human tissue analyses. Using the Four Core Genotype (FCG) mouse model, we will dissect the independent and interactive roles of sex chromosomes and hormones in DMET regulation. The 4-vinylcyclohexene diepoxide (VCD) model will allow us to examine the effects of menopause-related hormonal shifts on DMET expression and activity. Finally, we will analyze human liver, intestine, and kidney tissues to reveal comprehensive sex-specific DMET patterns in human. This research will redefine our understanding of sex-dependent drug metabolism and transport, informing evidence-based drug dosing strategies that enhance treatment efficacy and safety. Moreover, this study will lay a critical foundation for future clinical research, ensuring broader applicability across populations and advancing personalized medicine.