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JL Emmrich, MM Henry, CM B Skumatz, JM Burke, JT Eells; Formic Acid Induced Photoreceptor Toxicity . Invest. Ophthalmol. Vis. Sci. 2002;43(13):4534.
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Purpose:Methanol is an important health and environmental concern because of the neurotoxic actions of its metabolite, formic acid. Formic acid has been hypothesized to act as a mitochondrial toxin to produce retinal and optic nerve toxicity. Studies in our laboratory using a methanol-sensitive rodent model have revealed functional, metabolic and structural abnormalities in the retina consistent with this hypothesis. Cellular acidosis induced by the accumulation of weak organic acids like formic acid may contribute to retinal toxicity. The present studies were undertaken to further define the mechanism of formic acid toxicity by comparing the cellular consequences of sodium formate and formic acid exposure in cultured photoreceptors. Methods: A photoreceptor cell line (661W cells) was exposed to either sodium formate (30 mM, pH 7.4) or formic acid (30 mM, pH 6.9). Cellular formate concentrations, cellular ATP concentrations and cell viability were assessed at 2 h and 24 h. Results: Intracellular formate concentrations increased from basal concentrations of 3 0.5 µmoles formate/mg protein to 38 4 µmoles formate/mg protein following 2 hours of exposure to either formate or formic acid. However, by 24 h of exposure intracellular formate concentrations were significantly greater in cells exposed to formic acid than in cells exposed to sodium formate. (50 5 µmoles formate/mg protein vs 17 2 µmoles formate/mg protein). Intracellular ATP concentrations were significantly decreased in cells exposed to formic acid following 2 hr (70% of control) or 24 hr (50% of control) of exposure. ATP concentrations were not altered in cells exposed to sodium formate. Significant decreases in cell viability as assessed by propidium iodide staining were also apparent at 2 h in formic acid exposed cultures, but not in sodium formate exposed cultures. Conclusion: These data provide evidence for pH dependent differences in the cytotoxic actions of formate. They are consistent with studies showing that the undissociated formic acid is the active inhibitor of mitochondrial cytochome oxidase and that formic acid is only permeable through the inner mitochondrial membrane in its undissociated form. (Supported by NIH RO1-ES06648, RO1-EY11396, P30-EY01931).
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