Mitochondrial permeability transition as a potential determinant of hepatotoxicity of antidiabetic thiazolidinediones

Area of Science:

• Biochemistry
• Pharmacology
• Toxicology

Background:

• Troglitazone, a thiazolidinedione antidiabetic drug, is known to cause severe idiosyncratic hepatotoxicity.
• The mechanism underlying troglitazone-induced liver injury, particularly the role of reactive metabolites and mitochondrial dysfunction, remains incompletely understood.
• Previous studies suggest troglitazone induces cytotoxicity and mitochondrial dysfunction in hepatocytes.

Purpose of the Study:

• To investigate the effects of troglitazone and related thiazolidinediones on mitochondrial function.
• To determine if troglitazone-induced mitochondrial dysfunction contributes to its hepatotoxicity.
• To compare the effects of troglitazone with less hepatotoxic thiazolidinediones like rosiglitazone and pioglitazone.

Main Methods:

• Isolated liver mitochondria fractions from male CD-1 mice were used.
• Mitochondrial function was assessed by measuring swelling, membrane potential, and Ca2+ accumulation.
• The effects of troglitazone, ciglitazone, rosiglitazone, and pioglitazone were evaluated, with and without cyclosporin A.

Main Results:

• Troglitazone induced mitochondrial swelling, decreased mitochondrial membrane potential, and impaired mitochondrial Ca2+ accumulation.
• These effects indicate that troglitazone induces mitochondrial permeability transition (MPT).
• Ciglitazone showed similar effects, while rosiglitazone and pioglitazone had minimal impact on mitochondrial function.

Conclusions:

• Troglitazone induces mitochondrial permeability transition (MPT) in isolated mouse liver mitochondria.
• The MPT pore opening induced by troglitazone may be a key mechanism contributing to its specific hepatotoxicity.
• The lack of MPT induction by rosiglitazone and pioglitazone correlates with their lower hepatotoxic potential.