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Mitochondrial respiratory chain dysfunction, a non-receptor-mediated effect of synthetic PPAR-ligands: biochemical and pharmacological implications.
- Source :
-
Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2004 Jul 02; Vol. 319 (3), pp. 967-73. - Publication Year :
- 2004
-
Abstract
- Peroxisome proliferator activated receptors (PPARs) are a class of nuclear receptors involved in lipid and glucidic metabolism, immune regulation, and cell differentiation. Many of their biological activities have been studied by using selective synthetic activators (mainly fibrates and thiazolidinediones) which have been already employed in therapeutic protocols. Both kinds of drugs, however, showed pharmacotoxicological profiles, which cannot be ascribed by any means to receptor activation. To better understand these non-receptorial or extrareceptorial aspects, the effect of different PPAR-ligands on the metabolic status of human HL-60 cell line has been investigated. At this regard, NMR analysis of cell culture supernatants was accomplished in order to monitor modifications at the level of cell metabolism. Cell growth and chemiluminescence assays were employed to verify cell differentiation. Results showed that all the considered PPAR-ligands, although with different potencies and independently from their PPAR binding specificity, induced a significant derangement of the mitochondrial respiratory chain consisting in a strong inhibition of NADH-cytochrome c reductase activity. This derangement has been shown to be strictly correlated to the adaptive metabolic modifications, as evidenced by the increased formation of lactate and acetate, due to the stimulation of anaerobic glycolysis and fatty acid beta-oxidation. It is worthy noting that the mitochondrial dysfunction appeared also linked to the capacity of any given PPAR-ligand to induce cell differentiation. These data could afford an explanation of biochemical and toxicological aspects related to the therapeutic use of synthetic PPAR-ligands and suggest a revision of PPAR pathophysiologic mechanisms.
- Subjects :
- Bezafibrate pharmacology
Cell Differentiation physiology
Cell Division physiology
Clofibric Acid pharmacology
Dose-Response Relationship, Drug
Electron Transport drug effects
Gemfibrozil pharmacology
HL-60 Cells metabolism
Humans
Hypoglycemic Agents pharmacology
Hypolipidemic Agents pharmacology
Mitochondria drug effects
Thiazolidinediones pharmacology
Electron Transport physiology
Ligands
Mitochondria metabolism
Receptors, Cytoplasmic and Nuclear metabolism
Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0006-291X
- Volume :
- 319
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Biochemical and biophysical research communications
- Publication Type :
- Academic Journal
- Accession number :
- 15184076
- Full Text :
- https://doi.org/10.1016/j.bbrc.2004.05.072