Sublethal stress from polypharmacy modulates scavenging function and fenestrations in mouse liver sinusoidal...

Area of Science:

• Hepatology
• Pharmacology
• Cell Biology

Background:

• Polypharmacy is common in older adults, increasing risks of adverse health outcomes.
• Liver sinusoidal endothelial cells (LSECs) maintain liver function by regulating fenestrations.
• Drug metabolism can alter LSEC function, potentially leading to hepatic disorders.

Purpose of the Study:

• To investigate the impact of four common drugs (metoprolol, citalopram, oxybutynin, oxycodone) on LSEC function.
• To assess drug effects on LSEC viability, endocytosis, and fenestration morphology.
• To model polypharmacy by examining drug combinations at systemic and first-pass concentrations.

Main Methods:

• In vitro study using LSEC models.
• Exposure to individual drugs and a polypharmacy cocktail.
• Assessment of LSEC viability, endocytosis, and fenestration integrity.
• Evaluation at systemic steady-state and first-pass drug concentrations.

Main Results:

• All tested drugs caused sublethal metabolic changes in LSECs.
• Citalopram and oxybutynin induced dose-dependent defenestration.
• Metoprolol and oxycodone showed mild, non-dose-dependent effects on fenestrations.
• Endocytic activity increased with oxybutynin, metoprolol, oxycodone, and the polypharmacy cocktail.
• The polypharmacy cocktail exhibited synergistic defenestration at first-pass concentrations.

Conclusions:

• Drug-specific and concentration-dependent effects on LSECs were observed.
• Polypharmacy can lead to synergistic disruption of LSEC fenestrations, particularly during first-pass metabolism.
• Endothelial dysfunction in LSECs is a potential mechanism for drug-induced liver injury, necessitating consideration in drug safety assessments.