Reactive oxygen intermediates are produced in all aerobic organisms during respiration and exist in the cell in a balance with biochemical antioxidants. Excess reactive oxygen resulting from exposure to environmental oxidants, toxicants, and heavy metals perturbs cellular redox balance and disrupts normal biological functions. The resulting imbalance may be detrimental to the organism and contribute to the pathogenesis of disease and aging. To counteract the oxidant effects and to restore a state of redox balance, cells must reset critical homeostatic parameters. Changes associated with oxidative damage and with restoration of cellular homeostasis often lead to activation or silencing of genes encoding regulatory transcription factors, antioxidant defense enzymes, and structural proteins. In this review, we examine the sources and generation of free radicals and oxidative stress in biological systems and the mechanisms used by reactive oxygen to modulate signal transduction cascades and redirect gene expression.

Regulation of gene expression by reactive oxygen

Chelation therapy is the preferred medical treatment for reducing the toxic effects of metals. Chelating agents are capable of binding to toxic metal ions to form complex structures which are easily excreted from the body removing them from intracellular or extracellular spaces. 2,3-Dimercaprol has long been the mainstay of chelation therapy for lead or arsenic poisoning, however its serious side effects have led researchers to develop less toxic analogues. Hydrophilic chelators like meso-2,3-dimercaptosuccinic acid effectively promote renal metal excretion, but their ability to access intracellular metals is weak. Newer strategies to address these drawbacks like combination therapy (use of structurally different chelating agents) or co-administration of antioxidants have been reported recently. In this review we provide an update of the existing chelating agents and the various strategies available for the treatment of heavy metals and metalloid intoxications.

http://www.tracemin.com/fileadmin/uploads/pdf/en/Chelation_in_Metal_Intoxication.pdf

Chelation in Metal Intoxication

Recent studies have shown that lead causes oxidative stress by inducing the generation of reactive oxygen species, reducing the antioxidant defense system of cells via depleting glutathione, inhibiting sulfhydryl-dependent enzymes, interfering with some essential metals needed for antioxidant enzyme activities, and/or increasing susceptibility of cells to oxidative attack by altering the membrane integrity and fatty acid composition. Consequently, it is plausible that impaired oxidant/antioxidant balance can be partially responsible for the toxic effects of lead. Where enhanced oxidative stress contributes to lead-induced toxicity, restoration of a cell's antioxidant capacity appears to provide a partial remedy. Several studies are underway to determine the effect of antioxidant supplementation following lead exposure. Data suggest that antioxidants may play an important role in abating some hazards of lead. To explain the importance of using antioxidants in treating lead poisoning the following topics are addressed: (i) Oxidative damage caused by lead poisoning; (ii) conventional treatment of lead poisoning and its side effects; and (iii) possible protective effects of antioxidants in lead toxicity.

Can antioxidant be beneficial in the treatment of lead poisoning

https://web.mst.edu/~nercal/documents/publications/40.pdf

Can Antioxidants Be Beneficial in the Treatment of Lead Poisoning

Antioxidant nutrients and lead toxicity.

In vivo indices of oxidative stress in lead-exposed C57BL/6 mice are reduced by treatment with meso-2,3-Dimercaptosuccinic Acid or N-acetylcysteine

Evidence implicating oxidative stress in toxicity during lead intoxication in vivo has opened new avenues for investigation of the mechanisms of lead-induced immunosuppression. The current study explores the possibility that lead-induced oxidative stress contributes to the immunosuppression observed during lead poisoning. Fisher 344 rats were exposed to 2,000 ppm lead acetate in their drinking water for 5 weeks. One week following removal of lead from the drinking water, significant reductions in serum levels of IgA, IgM, and IgG were detected. Significant increases in oxidative damage, based on malondialdehyde (MDA) content, were observed in peripheral blood mononuclear cells (PMCs) collected during the same experiments. In addition, MDA content increased in livers from lead-exposed rats. Following 5 weeks of lead exposure, administration of either 5.5 mmol/kg N-acetylcysteine (NAC) or 1 mmol/kg meso-2,3-dimercaptosuccinic acid (DMSA) in the drinking water for 1 week significantly reversed the inhibitory effects of lead on serum immunoglobulin (Ig) levels. Also, all parameters indicative of oxidative stress returned to control levels. These results suggest that oxidative stress contributes to suppressed serum Ig levels during lead intoxication in vivo, and that intervention with either a thiol antioxidant (NAC) or a metal chelator (DMSA) will alleviate this lead-induced suppression by correcting the prooxidant/antioxidant imbalance caused by lead exposure.

/pdf/a-role-for-oxidative-stress-in-suppressing-serum-hy6wjqhq3f.pdf

A role for oxidative stress in suppressing serum immunoglobulin levels in lead-exposed Fisher 344 rats.

https://web.mst.edu/~nercal/documents/publications/22.pdf

N-acetylcysteine protects Chinese hamster ovary (CHO) cells from lead-induced oxidative stress

A new method for the determination of reduced and oxidized glutathione by using capillary zone electrophoresis was developed and compared with the N-(1-pyrenyl)maleimide high-performance liquid chromotography method. The tissue samples were obtained from C57BL/6 mice and homogenized in deionized water. The detection wavelength was set at 214 nm. A 50-cm effective length x 75 microns i.d. uncoated fused silica capillary with a 10 mM phosphate buffer at pH 7.5 was used for the experiment. Samples were introduced by pressure injection for 5s. The voltage for separation was at 20 kV. Between runs, the capillary was regularly washed with 0.1 N NaOH and deionized water, followed by reconditioning with running buffer. The present method was shown to be reproducible and is convenient in that a derivatization step is not required. The method has been used to measure glutathione levels in biological samples and the results show good agreement with those obtained by high-performance liquid chromotography.

/pdf/analysis-of-thiol-containing-compounds-in-biological-samples-3b294kp6s1.pdf

Piyanee Treeratphan

Papers

In vivo indices of oxidative stress in lead-exposed C57BL/6 mice are reduced by treatment with meso-2,3-Dimercaptosuccinic Acid or N-acetylcysteine

A role for oxidative stress in suppressing serum immunoglobulin levels in lead-exposed Fisher 344 rats.

N-acetylcysteine protects Chinese hamster ovary (CHO) cells from lead-induced oxidative stress

Analysis of thiol-containing compounds in biological samples by capillary zone electrophoresis