Mitochondria, ciglitazone and liver: A neglected interaction in biochemical pharmacology

Peroxisome proliferator activated receptors (PPARs) are a class of nuclear receptors now actively investigated for their involvement in lipid and glucidic metabolism, immune regulation and cell differentiation. Drugs binding and activating PPARs are therefore attracting attention for their potential therapeutic role in various diseases like type 2 diabetes, dyslipidemias, atherosclerosis, obesity (i.e., metabolic syndrome). Agonists of these receptors have been already used in therapeutic protocols: fibrates (PPAR-α ligands) are being used in hyperlipidemias, and thiazolidinediones (mainly PPAR-γ ligands) are being employed as insulin sensitizers. The latter drugs introduction into therapy, however, showed very soon some unwanted effects (hepatotoxicity at first and myocardiotoxicity later on) which confirmed some contradictory data already suggested by pre-clinical trial-experiments. In this study we show that some PPAR ligands impair mitochondrial oxidative metabolism in human liver cell line mainly by deranging NADH oxidation. Intriguingly, the PPAR-γ ligand ciglitazone caused a dose-dependent inhibition of NADH-cytochrome c reductase that resulted, at a drug concentration of 50 μM, of about 60% (P < 0.001), while other PPAR ligands with different receptor affinity – positive controls like clofibrate (0.7 mM), gemfibrozil (0.23 mM) and bezafibrate (1 mM) – reduced the activity of mitochondrial Complex I by about 20% (P < 0.01, P < 0.01 and P < 0.05, respectively). The induced mitochondrial dysfunction imposed a series of metabolic compensatory adaptations characterized by a significant shift to anaerobic glycolysis. These findings underline the undervalued non-genomic effects of PPAR ligands and can provide a better understanding of the pharmacotoxicological profiles of these drugs and of their roles in the therapy of diabetes mellitus.