Relationship between coumarin-induced hepatocellular toxicity and mitochondrial function in rats

Area of Science:

• Hepatotoxicity
• Toxicology
• Biochemistry

Background:

• Coumarin-induced liver injury in rats presents differently based on dosing frequency.
• Single doses cause hepatocellular necrosis, whereas repeated doses lead to hepatocyte degeneration.
• The underlying mechanisms of these varied toxic effects remain incompletely understood.

Purpose of the Study:

• To investigate the mechanistic differences in coumarin-induced hepatotoxicity following single versus repeated dosing in male rats.
• To elucidate the roles of mitochondrial function and cytochrome P450 2E1 (CYP2E1) expression in coumarin toxicity.

Main Methods:

• Male rats received either a single coumarin dose or coumarin for four consecutive days.
• Liver samples were collected at various time points (4h, 24h post-single dose; 24h post-repeated dose).
• Evaluated hepatocellular damage, mitochondrial morphology and function, and CYP2E1 protein expression.

Main Results:

• A single coumarin dose induced significant hepatocellular necrosis, linked to increased mitochondrial number/size and decreased mitochondrial function.
• Increased granular CYP2E1 protein expression was observed in the cytoplasm and mitochondria after a single dose.
• Repeated dosing attenuated toxicity, with mitochondrial function comparable to controls and CYP2E1 protein distributed outside mitochondria.

Conclusions:

• Mitochondrial dysfunction and altered CYP2E1 expression are implicated in coumarin-induced hepatotoxicity.
• Reduced mitochondrial CYP2E1 may contribute to the development of coumarin resistance after repeated exposure.