Reactive metabolite activation by CYP2C19-mediated rhein hepatotoxicity

Area of Science:

• Pharmacology
• Toxicology
• Hepatology

Background:

• Rhein, a rhubarb root compound, has therapeutic uses but is linked to hepatotoxicity.
• Rhein's toxicity may stem from reactive metabolites (RMs) formed during its metabolism.
• Understanding the mechanism of rhein-induced liver injury is crucial for patient safety.

Purpose of the Study:

• To investigate the role of reactive metabolites (RMs) in rhein-induced hepatotoxicity.
• To identify the specific metabolic enzymes involved in rhein activation.
• To elucidate the mechanism underlying rhein's liver injury.

Main Methods:

• Utilized IC50 shift and glutathione (GSH) trapping experiments to detect RMs.
• Established a primary rat hepatocyte model with reduced CYP450 enzyme activity.
• Assessed cytotoxicity, mitochondrial dysfunction, and restored parameters using CYP2C19 inhibitors.

Main Results:

• CYP2C19 was identified as a primary enzyme activating rhein into an epoxide RM.
• Rhein induced mitochondrial dysfunction and elevated AST levels.
• Inhibition of CYP2C19 reversed rhein-induced mitochondrial dysfunction and hepatotoxicity.

Conclusions:

• CYP2C19-mediated activation of rhein to RMs is a key mechanism of its hepatotoxicity.
• This finding provides insights into predicting drug-induced liver injury (DILI).
• Targeting CYP2C19 may offer a strategy to mitigate rhein-induced liver damage.