Caffeine and acetaminophen association: Effects on mitochondrial bioenergetics

Area of Science:

• Biochemistry
• Toxicology
• Mitochondrial Biology

Background:

• Acetaminophen (APAP) overdose is a leading cause of acute liver injury.
• Mitochondrial dysfunction plays a critical role in APAP-induced hepatotoxicity.
• Caffeine is frequently co-ingested with APAP, but its effects on APAP hepatotoxicity are not fully understood.

Purpose of the Study:

• To investigate the impact of combined acetaminophen (APAP) and caffeine administration on hepatic mitochondrial bioenergetic function in a mouse model.
• To elucidate the potential protective mechanisms of caffeine against APAP-induced liver injury at the mitochondrial level.

Main Methods:

• Mice received intraperitoneal injections of caffeine (20mg/kg) followed 30 minutes later by APAP (250mg/kg) or their respective vehicles.
• Liver tissues were collected 4 hours post-APAP administration for analysis.
• Hepatic cellular oxygen consumption was assessed using high-resolution respirometry (HRR).
• Mitochondrial function, oxidative stress markers (lipid peroxidation, ROS, glutathione), and mitochondrial swelling were evaluated.

Main Results:

• Acetaminophen (APAP) treatment significantly reduced cellular oxygen consumption and mitochondrial complex activities in mouse livers.
• APAP administration led to increased mitochondrial swelling, lipid peroxidation, and reactive oxygen species (ROS) production, while decreasing glutathione levels.
• Co-administration of caffeine with APAP ameliorated these detrimental effects, improving hepatic mitochondrial bioenergetic function.
• Caffeine prevented the increase in lipid peroxidation and ROS production induced by APAP.

Conclusions:

• Caffeine exhibits protective effects against acetaminophen (APAP)-induced hepatotoxicity in mice.
• The beneficial effects of caffeine may stem from its antioxidant properties and/or its direct interaction with mitochondrial bioenergetic pathways.
• These findings suggest caffeine could mitigate APAP-induced liver damage by preserving mitochondrial function and reducing oxidative stress.