Structural determinants of fluorochemical-induced mitochondrial dysfunction

摘要: Perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS) are thought to induce peroxisome proliferation interfere with mitochondrial metabolic pathways. Direct measurements revealed that PFOA the unsubstituted sulfonamide of perfluorooctane (FOSA) uncouple respiration by increasing proton conductance. The purpose this investigation was characterize structural determinants responsible for uncoupling effect several structurally related fluorochemicals. Included in study were PFOA, PFOS, FOSA, N-acetate FOSA (perfluorooctanesulfonamidoacetate, FOSAA), N-ethylperfluorooctanesulfonamide (N-EtFOSA), N-ethyl alcohol [2-(N-ethylperfluorooctanesulfonamido)ethyl alcohol, N-EtFOSE] N-acetic acid (N-ethylperfluorooctanesulfonamidoacetate, N-EtFOSAA) N-EtFOSA. Each test compound dissolved ethanol added directly an incubation medium containing substrateenergized rat liver mitochondria. Mitochondrial membrane potential measured concurrently using oxygen electrode a TPP 1 -selective electrode, respectively. All compounds tested, at sufficiently high concentrations, had capacity respiration, albeit via different mechanisms varying potencies. At free acids PFOS caused slight increase intrinsic leak inner membrane, which resembled surfactant-like change fluidity. Similar effects observed N-EtFOSE. Another fully substituted sulfonamide, N-EtFOSAA, concentrations inhibition release cytochrome c, high-amplitude swelling prevented cyclosporin A or EGTA, indicating induced permeability transition. monosubstituted amides N-EtFOSA, FOSAA all exerted strong on mitochondria resembling protonophoric uncouplers. Among these compounds, very potent uncoupler oxidative phosphorylation, IC50 approximately mM. These data suggest protonated nitrogen atom favorable pKa is essential action sulfonamides mitochondria, may be critical mechanism metabolism vivo.