Esterification Prevents Induction of the Mitochondrial Permeability Transition by N-Acetyl Perfluorooctane Sulfonamides
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- 作者：Timothy M. O'Brien ; Robert M. Carlson ; Paulo J. Oliveira ; Kendall B. Wallace
- 刊名：Chemical Research in Toxicology
- 出版年：2006
- 出版时间：October 2006
- 年：2006
- 卷：19
- 期：10
- 页码：1305 - 1312
- 全文大小：290K
- 年卷期：v.19,no.10(October 2006)
- ISSN：1520-5010
文摘
N-Alkyl perfluorooctane sulfonamides have been widely used as surfactants on fabrics and papers,fire retardants, and anticorrosion agents, among many other commercial applications. The broad use,global distribution, and environmental persistence of these compounds has generated considerable interestregarding potentially toxic effects. We have previously reported that perfluorooctanesulfonamidoacetate(FOSAA) and N-ethylperfluorooctanesulfonamidoacetate (N-EtFOSAA) induce the mitochondrial permeability transition (MPT) in vitro, resulting in cytochrome c release, inhibition of respiration, and generationof reactive oxygen species. By synthesizing the corresponding methyl esters of FOSAA and N-EtFOSAA(methyl perlfuorinated sulfonamide acetates), we tested the hypothesis that the N-acetate moiety of FOSAAand N-EtFOSAA is the functional group responsible for induction of the MPT. Swelling of freshly isolatedliver mitochondria from Sprague-Dawley rats was monitored spectrophotometrically and membranepotential (
) was measured using a tetraphenylphosphonium-selective (TPP+) electrode. In the presenceof calcium, 40 
M FOSAA and 7 M N-EtFOSAA each induced mitochondrial swelling and a biphasicdepolarization of membrane potential. Mitochondrial swelling and the second-phase depolarization wereinhibited by cyclosporin-A or the catalyst of K+/H+ exchange nigericin, whereas the first-phasedepolarization was not affected by either. In contrast, the methyl esters of FOSAA and N-EtFOSAAexhibited no depolarizing or MPT inducing activity. Results of this investigation demonstrate that thecarboxylic acid moiety of the N-acetates is the active functional group, which triggers the MPT byperfluorinated sulfonamides.
) was measured using a tetraphenylphosphonium-selective (TPP+) electrode. In the presenceof calcium, 40 M FOSAA and 7 M N-EtFOSAA each induced mitochondrial swelling and a biphasicdepolarization of membrane potential. Mitochondrial swelling and the second-phase depolarization wereinhibited by cyclosporin-A or the catalyst of K+/H+ exchange nigericin, whereas the first-phasedepolarization was not affected by either. In contrast, the methyl esters of FOSAA and N-EtFOSAAexhibited no depolarizing or MPT inducing activity. Results of this investigation demonstrate that thecarboxylic acid moiety of the N-acetates is the active functional group, which triggers the MPT byperfluorinated sulfonamides.