Liver metabolic pathways and drug metabolism

Liver Metabolism & Pharmacology

The liver is the first major organ exposed to many diet- and microbiome-derived metabolites and plays a central role in regulating whole-body metabolism and drug handling. We study how bioactive metabolites produced from diet and microbial activity influence hepatic physiology, including pathways involved in xenobiotic sensing, metabolic regulation, and drug clearance. A major goal of this work is to understand how variation in diet and microbiome activity contributes to inter-individual differences in pharmacology. Our recent work showed that microbiome-dependent metabolism of dietary phytochemicals can alter hepatic drug metabolism and reduce the efficacy of anticancer therapy (see Figure), highlighting a direct mechanistic link between nutrition, microbial chemistry, and pharmacokinetics. More broadly, we seek to define how the chemical environment reaching the liver shapes its function in health and disease, and how these processes can be leveraged to improve therapeutic response and precision medicine.

Soy-derived microbial metabolites shape PI3Ki pharmacokinetics and efficacy — Graphical summary of our recent findings showing how diet–microbiome interactions regulate hepatic drug metabolism and anticancer drug efficacy (Roichman et al., *Cell*, 2025). Gut microbial conversion of the dietary soy phytochemicals soyasaponins into soyasapogenols induces hepatic cytochrome P450 activity, lowers circulating PI3K inhibitor exposure, and reduces tumor control. In mice fed soy-free purified diets or treated with antibiotics, this pathway is disrupted, resulting in lower hepatic CYP activity, increased drug exposure, and improved tumor control.