Mitochondrial respiratory chain dysfunction, a non-receptor-mediated effect of synthetic PPAR-ligands: biochemical and pharmacological implications
Section snippets
Materials and methods
Cells and treatments. The human acute promyelocytic leukemia HL-60 cell line was obtained from Interlab Cell Line Collection (CBA, Genoa, Italy). Cells were maintained at 37 °C under a humidified atmosphere of 5% CO2 in RPMI 1640 Hepes modified medium supplemented with 10% (v/v) heat inactivated fetal calf serum, 2 mM glutamine, 100 IU/ml penicillin, and 100 μg/ml streptomycin. Cell number was determined using a Neubauer hemocytometer and viability was assessed by their ability to exclude trypan
Mitochondrial respiratory chain enzyme activities
All the considered PPAR-ligands inhibited significantly the mitochondrial respiratory chain at the level of NADH–cytochrome c reductase in a dose-dependent manner in digitonin permeabilized HL-60 cells and the efficiency of mitochondrial inhibition varied from ligand to ligand (Fig. 1). In fact, considering the inhibitory activity observed at 50 μmol (the concentration at which ciglitizone attains its highest effect and that approaches usual plasma concentration of the other ligands during
Discussion
Alternative biochemical activities of PPAR synthetic ligands, apart from receptor binding and activation, were taken into consideration in order to explain contradictory aspects of PPAR pathophysiology. The investigations that were therefore performed at this purpose gave results showing that all the considered PPAR-ligands inhibited the electron transport chain of mitochondria of digitonin permeabilized HL-60 cells at the level of NADH–cytochrome c reductase in a dose-dependent manner.
To say
Acknowledgements
The authors thank Prof. Paolo Sarti (Università La Sapienza di Roma) for his support and helpful comments.
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