Mercury toxicity and antioxidants: part I: role of glutathione and alpha-lipoic acid in the treatment of mercury toxicity - Mercury Toxicity - Brief Article

Alternative Medicine Review, Dec, 2002 by Lyn Patrick

ALA has been administered to humans in doses up to 1,200 mg intravenously without toxicity, and in oral daily doses of as much as 600 mg three times daily. The only side effects reported are infrequent nausea and vomiting. No side effects have been reported in oral administration of up to 1,800 mg daily. (41,48) Doses of 500-1,000 mg have been well tolerated in placebo-controlled studies. (49) Extrapolation of pharmacokinetic and toxicity data demonstrate safe human dosages would not be exceeded with oral doses of several grams per day. (41)

ALA has been shown to increase both intra- and extracellular levels of glutathione in T-cell cultures, human erythrocytes, glial cells, and peripheral blood lymphocytes. (50) In rats, oral dosing of 150 mg/kg/day for eight weeks significantly increased glutathione levels in the blood and liver. (51) ALA has been shown to increase intracellular glutathione by 30-70 percent in murine neuroblastoma and melanoma cell lines, and in the lung, liver, and kidney cells of mice that had received intraperitoneal injections of 4, 8, or 16 mg/ kg ALA for 11 days. (52,53) Levels of intracellular glutathione have been shown to increase by 16 percent in T-cell cultures at concentrations of 10-100 [micro]M (concentrations achievable with oral and intravenous supplementation of ALA). (50) A single oral dose of 600 mg ALA was able to produce a serum concentration of 13.8 [ or -] 7.2 [micro]M and levels of 100-200 [micro]M have been reported after 600 mg intravenous administration. (54)

Increases in glutathione levels seen with ALA administration are not only from the reduction of oxidized glutathione (one of the functions of ALA) but also from the synthesis of glutathione. (46) ALA is reduced to dihydrolipoic acid (DHLA), itself a potent antioxidant. DHLA is able to regenerate oxidized ascorbate, glutathione, coenzyme Q, and vitamin E, (28) and is responsible for the ability of ALA to increase intracellular glutathione levels (Figure 1). (55)

[FIGURE 1 OMITTED]

ALA, through its reduction to DHLA and oxidation back to ALA, has the ability to continuously provide cysteine, the rate-limiting amino acid for glutathione production. ALA is rapidly reduced to DHLA and released in the extracellular environment where it reduces extracellular cystine to cysteine and increases the uptake of cysteine into the cell, (50) increasing glutathione production. ALA does this through enzyme-catalyzed reactions using NADH or NADPH, the metabolic power resulting from glucose metabolism (Figure 2). (51)

[FIGURE 2 OMITTED]

ALA and Binding of Copper, Iron, Platinum, and Lead

ALA and DHLA have been shown to form complexes with manganese (Mn[2.sup. ]), zinc (Zn[2.sup. ]), cadmium (Cd[2.sup. ]), lead (Pb[2.sup. ]), cobalt (Co[2.sup. ]), nickel (Ni[2.sup. ]), and iron (Fe[2.sup. ]) ions. (55) In many cases, ALA-mediated heavy-metal binding prevents free-radical caused tissue damage or enzyme inactivation. (56)

In the case of iron and copper, complexing with ALA can protect cells from damage caused by iron- or copper induced lipid peroxidation. (41) ALA has been shown to bind copper in human lipoproteins (57) and, as a result, to inhibit copper-induced peroxidation of low density lipoproteins. ALA has been used to treat Wilson's disease, effectively increasing renal copper excretion and normalizing liver function. (58)