Reprogramming of Hepatic Drug Metabolism following Early-life Xenobiotic Exposure: Insights from Nuclear Receptor Pathways.

Substantial interindividual variability in the expression and activity of drug-metabolizing enzymes (DMEs) contributes to variability in drug disposition and response. Early-life, encompassing the fetal and neonatal periods, is a critical developmental window for the establishment and functional programming of the hepatic DME system. Exposure to xenobiotics such as pharmaceuticals, environmental pollutants, inflammatory mediators, and nutritional interventions during this vulnerable period can exert long-term programming effects on hepatic drug metabolism. These effects are mediated primarily through the disruption of nuclear receptor signaling networks, ultimately altering hepatic drug-metabolizing capacity and potentially influencing susceptibility to altered drug responses in later life. This review systematically examines the pivotal roles of the constitutive androstane receptor, pregnane X receptor, and glucocorticoid receptor in mediating the reprogramming of DME expression following early-life xenobiotic exposure. Furthermore, it delineates how epigenetic reprogramming, with a particular focus on histone modifications, converts nuclear receptor-derived signals into persistent transcriptional memories, thereby consolidating the long-term phenotypic effects of early-life events. Additionally, the review integrates evidence on how endogenous factors, including inflammation and nutritional status, modulate drug metabolic programming by regulating nuclear receptor networks. Framed within the Developmental Origins of Health and Disease paradigm, this review elucidates the mechanistic foundations of interindividual differences in drug responses. The insights provided herein aim to provide a critical scientific basis for understanding the long-term consequences of early-life exposure and informing future research on risk assessment and translational evaluation.