Circadian regulation of hepatic detoxification: implications for drug-induced liver injury.

The hepatic capacity for xenobiotic detoxification exhibits pronounced circadian rhythmicity. The molecular basis of this rhythm lies in the autonomous transcriptional-translational feedback loops constituted by clock-controlled genes (CCGs). These loops temporally regulate the expression of a vast array of drug-metabolizing enzymes (DMEs) and transporters, thereby determining the liver's detoxification efficacy at different times of day. Dysfunction of CCGs, such as reverse erythroblastosis virus α (Rev-erbα), brain and muscle ARNT-like 1 (Bmal1), circadian locomotor output cycles kaput (Clock), and period (Per), directly disrupts this metabolic timing and alters the liver's susceptibility to specific toxicants. Therefore, this review elaborates on the circadian characteristics of hepatic detoxification function, analyzes the complex network through which CCGs regulate hepatotoxicity, and further explores how external zeitgebers (e.g., light, food) and the timing of drug administration influence the outcomes of liver injury by either synchronizing or disrupting endogenous rhythms. These findings provide a theoretical basis for applying chronopharmacological principles to prevent and mitigate drug-induced liver injury through time-based intervention strategies, such as optimizing drug administration timing and managing lifestyle factors.