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and proteins complexed with the toxic metals.27 (For more information on free radicals see: Neustadt J. “Antioxidants: Redefining their roles.” IMCJ 5.6:22-26.) Mitochondrial Damage One major mechanism for metals toxicity appears to be direct and indirect damage to mitochondria via depletion of glutathione, an endogenous thiol-containing (SH-) antioxidant, which results in excessive free radical generation and mitochondrial damage.28 Anecdotally, Dr Neustadt, in his clinic, frequently observes an elevation of urinary pyroglutamate, an organic acid that is a specific marker for glutathione depletion in patients with confirmed mercury toxicity.29 Not surprisingly, these patients also complain of fatigue, a hallmark symptom of mitochondrial damage. Mercury can accumulate in mitochondria and causes granular inclusions, which are visible with a scanning electron micrograph.30 Oxidative stress occurs in vitro and in vivo from both organic and inorganic mercury via

their high affinity for binding thiols (sulfur-containing molecules) and the depletion of mitochondrial glutathione.27 The central nervous system is particularly sensitive to damage by MeHg-induced glutathione depletion. In one study, ex vivo human neurons, astrocytes, and neuroblastoma cells were exposed for 24 hours to various levels of MeHg. The

LC50 (concentration at which 50% of the cells died) was 6.5, 8.1, and 6.9 ìM, respectively.28 A second ex vivo study of mouse neurons and astrocytes confirmed the lower LC50 concentration for neurons,31 and another vivo rat-brain study demonstrated mitochondrial respiratorychain damage.32 An in vitro, dose-response study of glutathione depletion and the LC50 of human neurons, astrocytes, and neuroblastoma cells exposed to MeHg showed an indirect relationship between GSH depletion and cell death and a direct relationship between length of MeHg exposure and cell damage. 28 Cell were exposed to 6.5, 8.1, and 6.9 ìM MeHg for 7 days. After 24 hours of exposure to MeHg, the LC50 for neurons, astrocytes and neuroblastoma cells was 6.5 (4.9–8.6), 8.1 (7.2–9.1), and 6.9 (6.4–7.5) ìM, respectively; after 48 hours it was 3.7 (3.2–4.3), 7.4 (6.9–7.9), and 5.5 (5.0–6.0) ìM, respectively; after 72 hours it was 2.9 (2.4–3.5), 7.0 (6.2–7.9), and 2.2 (0.5–8.9) ìM, respectively; and after 7 days of exposure to MeHg it was 2.4 (1.5–3.6) and 4.4 (1.0–19.5) ìM, respectively (toxicity of neuroblastoma cells after 7 days of exposure was not determined). Addition of buthionine sulfoximine (BSO), a glutathione-depleting agent, prior to MeHg exposure significantly increased the cytotoxicity of MeHg in all cell lines (P<.001). In contrast, pre-incubation with 1 mM GSH for 24 hours, followed by 10 ìM MeHg, resulted in protection of all cell lines from gross damage detected by phase-contrast microscopy.