Speaker
Description
Background: Sleep deprivation (SD) impairs diverse physiological functions and contributes to multi-system disorders, emerging as a prevalent public health concern. It has been demonstrated that SD disrupts metabolic homeostasis and drives liver disease progression, from non-alcoholic fatty liver disease to hepatocellular carcinoma. However, the consequences of SD on hepatic cytochrome P450 (CYP) remain poorly characterized.
Methods: Acute (ASD) and chronic (CSD) SD models were established in C57BL/6 mice using the modified multiple-platform method. Liver injury and inflammation were characterized by serum biochemistry, hepatic histology, and inflammatory cytokine mRNA expression. Hepatic CYP expression was quantified by RT-qPCR and Western blotting. CYP activities were evaluated using hepatic microsomal incubations and in vivo probe drug pharmacokinetics, with metabolites measured by LC-MS.
Results: Neither ASD nor CSD induced hepatic inflammation or injury. ASD significantly decreased the hepatic expression of CYP3A11. LC-MS analysis revealed significantly reduced in vitro formation of 6β-hydroxytestosterone and decreased in vivo exposure of oxidized nifedipine, indicating marked suppression of CYP3A activity in ASD. Conversely, CYP2D9 expression was significantly downregulated in CSD, accompanied by reduced dextrorphan formation in microsomal incubations and decreased systemic exposure in vivo, collectively demonstrating impaired CYP2D9 catalytic function in CSD.
Conclusion: This study demonstrates that ASD selectively downregulates CYP3A11 expression and activity, whereas CSD markedly inhibits CYP2D9. These findings provide a potential mechanistic basis for altered drug efficacy and toxicity in sleep-deficient populations and inform rational drug use.
