Mitochondrial permeability transition as the critical target of N-acetyl perfluorooctane sulfonamide toxicity in vitro
| Autor: | Timothy M. O'Brien, Kendall B. Wallace |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Male
Membrane permeability Bioenergetics Mitochondria Liver Mitochondrion In Vitro Techniques Toxicology Permeability Structure-Activity Relationship Respiration Animals chemistry.chemical_classification Reactive oxygen species Fluorocarbons Sulfonamides biology Chemistry Cytochrome c Cytochromes c Rats Mitochondrial permeability transition pore Biochemistry Toxicity biology.protein Caprylates Mitochondrial Swelling |
| Zdroj: | Toxicological sciences : an official journal of the Society of Toxicology. 82(1) |
| ISSN: | 1096-6080 |
| Popis: | Perfluorooctanyl compounds with active functional groups have been shown to disrupt mitochondrial bioenergetics by three distinct mechanisms: protonophoric uncoupling of mitochondrial respiration, induction of the mitochondrial permeability transition (MPT), or a nonselective increase in membrane permeability. The purpose of this investigation was to identify the initial target and specific sequence of events associated with the N-acetyl substituted perfluorooctanesulfonamides induced MPT. N-acetyl-perfluorooctanesulfonamide (FOSAA), N-ethyl-N-acetyl-perfluorooctanesulfonamide (N-Et FOSAA), perfluorooctanoic acid (PFOA), perfluorooctanesulfonate (PFOS), and N-ethyl-N-(2-ethoxy)-perfluorooctanesulfonamide (N-Et FOSE) were added individually to liver mitochondria freshly isolated from Sprague-Dawley rats. Mitochondrial swelling and cytochrome c release were recorded spectrophotometrically, oxygen uptake was monitored with a Clark-type oxygen electrode, and reactive oxygen species (ROS) were monitored by dichlorodihydrofluorescein diacetate (H(2)DCFDA) fluorescence. FOSAA (45 microM) and N-Et FOSAA (7.5 microM) induced calcium-dependent mitochondrial swelling, the release of cytochrome c, inhibition of uncoupled mitochondrial respiration, and ROS generation, all of which were inhibited by cyclosporin-A (CsA). PFOA (200 microM) displayed slight CsA sensitive activity, but neither PFOS (10 microM) nor N-Et FOSE (70 microM) induced the MPT. Results of this investigation demonstrate two important findings: (1) MPT induction is specific to the N-acetyl substituted perfluorooctanesulfonamides and, (2) the sequence of events is initiated by induction of the MPT, which causes the release of cytochrome c as well as other cofactors leading to inhibition of respiration and ROS generation. The toxicity of N-acetyl perfluorooctanyl compounds may therefore reflect the mitochondrial dysfunction, which is compounded by the ensuing oxidative injury. |
| Databáze: | OpenAIRE |
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