Pharm Sci. 2015;20(4): 169-174.
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Original Research

Mitochondrial Dysfunction as a Mechanism for Pioglitazone-Induced Injury toward HepG2 Cell Line 

Hossein Niknahad, Reza Heidari, Abdolsalam Mohammad Alzuhairi, Asma Najibi *


Background: Thiazolidinediones (TZDs) are widely used for treatment of type II diabetes mellitus in humans. The first drug of this class, troglitazone, was withdrawn from the market due to a high incidence of hepatotoxicity. Several cases of liver injury induced by other TZDs such as pioglitazone is also reported. The mechanism of cellular injury induced by pioglitazone is not recognized precisely so far. Mitochondria is a postulated target for TZDs to induce injury. Methods: This investigation was designed to evaluate the cytotoxic effects of pioglitazone in cultured HepG2 cells. Cell death, glutathione level, occurrence of lipid peroxidation, and finally cellular adenosine triphosphate (ATP) content, as an index of mitochondrial functionality, were monitored in HepG2 cells after pioglitazone administration. Results: It was found that pioglitazone was toxic towards HepG2 cells concentration dependently and 1 mM of pioglitazone reduced cellular viability to less than 60% in 48 hours of incubation. Pioglitazone administration reduced ATP content of the cells, but did not induce oxidative stress in this cell line, as no lipid peroxidation and/or decrease in cellular glutathione were detected. Administration of ATP suppliers dihydroxyacetone (5 and 10 mM) and glyceraldehyde (1 and 5 mM), inhibited drop in cellular ATP induced by pioglitazone and prevented drug-induced cell death. Conclusion: These results suggest that pioglitazone affect cellular mitochondria and might cause cytotoxicity by prevention of ATP production.
Keywords: Hepatotoxicity, Mitochondrial dysfunction, Pioglitazone, Thiazolidinediones, Drug-induced liver injury
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Submitted: 19 Feb 2015
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