Arsenic round the world: a review.

Advances in metal-induced oxidative stress and human disease

Arsenic toxicity and potential mechanisms of action

Arsenic (As) is a toxic metalloid element that is present in air, water and soil. Inorganic arsenic tends to be more toxic than organic arsenic. Examples of methylated organic arsenicals include monomethylarsonic acid [MMA(V)] and dimethylarsinic acid [DMA(V)]. Reactive oxygen species (ROS)-mediated oxidative damage is a common denominator in arsenic pathogenesis. In addition, arsenic induces morphological changes in the integrity of mitochondria. Cascade mechanisms of free radical formation derived from the superoxide radical, combined with glutathione-depleting agents, increase the sensitivity of cells to arsenic toxicity. When both humans and animals are exposed to arsenic, they experience an increased formation of ROS/RNS, including peroxyl radicals (ROO•), the superoxide radical, singlet oxygen, hydroxyl radical (OH•) via the Fenton reaction, hydrogen peroxide, the dimethylarsenic radical, the dimethylarsenic peroxyl radical and/or oxidant-induced DNA damage. Arsenic induces the formation of oxidized lipids which in turn generate several bioactive molecules (ROS, peroxides and isoprostanes), of which aldehydes [malondialdehyde (MDA) and 4-hydroxy-nonenal (HNE)] are the major end products. This review discusses aspects of chronic and acute exposures of arsenic in the etiology of cancer, cardiovascular disease (hypertension and atherosclerosis), neurological disorders, gastrointestinal disturbances, liver disease and renal disease, reproductive health effects, dermal changes and other health disorders. The role of antioxidant defence systems against arsenic toxicity is also discussed. Consideration is given to the role of vitamin C (ascorbic acid), vitamin E (α-tocopherol), curcumin, glutathione and antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase in their protective roles against arsenic-induced oxidative stress.

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Arsenic: toxicity, oxidative stress and human disease.

Toxicological profile for arsenic

There is currently no published chromatographic assay for the fentanyl family of analgesics. This study reports the development of a sensitive, precise, and accurate gas chromatographic method for the determination of fentanyl and its analogues in human plasma. Sensitivity attained for fentanyl and sufentanil was 0.1 ng/mL plasma with an average coefficient of variation of 4.5%. Calibration curve correlation coefficients of 0.99% or greater were consistently obtained. Average recovery of drug into the final extract exceeded 80% and was independent of fentanyl concentration. The required degree of specificity was obtained by selective extraction, use of the nitrogen/phosphorous detector, and chromatographic resolution. This method appears suitable for clinical studies of fentanyl and its derivatives in man.

Gas Chromatographic Determination of Fentanyl and its Analogues in Human Plasma

Determination and metabolism of dithiol chelating agents. VI. Isolation and identification of the mixed disulfides of meso-2,3-dimercaptosuccinic acid with L-cysteine in human urine.

The urinary excretion of meso-2,3-dimercaptosuccinic acid (DMSA), which is an effective chelating agent for lead, was determined after the oral administration of 10 mg DMSA/kg to six normal young men. The DMSA that was absorbed was extensively biotransformed. After 14 hours only 2.53% of the administered DMSA was excreted in the urine as unaltered DMSA and 18.1% as altered forms. The unaltered DMSA was 12% of the total DMSA found in the urine. The altered form(s) of DMSA was 88% of the total urinary DMSA. The altered DMSA can be converted to unaltered DMSA by electrolytic reduction, which indicates that the altered forms of DMSA are disulfides. The excretion of altered DMSA reached a peak between 2 and 4 hours after DMSA administration. There were small but statistically significant increases in the excretion of zinc, copper, and lead after DMSA administration. DMSA did not influence the urinary excretion of 27 other metals and elements.



Clinical Pharmacology and Therapeutics (1989) 45, 520–526; doi:10.1038/clpt.1989.67

Urinary excretion of meso‐2,3‐dimercaptosuccinic acid in human subjects

A simple and rapid method is presented for the quantitative determination of bromide and trifluoroacetlc acid in urine, plasma or serum. The biological-fluid Is treated with dimethyl sulfate in an acidic medium, resulting in thi~ formation of the methyl estei; of trifluoroacetic acid and methyl bromide. The volatile derivatives are then isolated from the samples via a head-space technique, separated and resolved by gas chromotography, and detected by flame ionization. Detection of the two metabolites Is:linear within the sample concentrations studied. The method is reproducible and applicable to the determination of the two metabolites in biological fluids in the 0.1-10 mM concentration range. The method is comparable to previous techniques but is less time consuming, and both bromide and trifluoroacetic acid can be determined simultaneously. Preliminary pharmacological studies of: urine: and blood metabolite "levels in rats and human patients anesthetized with halothane agree with existing results determined by other methods. In addition, the results indicate that bromide concentrations in human blood remain elevated for a much longer period of time than those in rat blood. head-space GC technique with flame-ionization detection (FID). The method does not require extraction, separation, sample transfer, lyophilization or other isolation procedures which would result in losses of the two metabolites.

R M Maiorino

Papers

Gas Chromatographic Determination of Fentanyl and its Analogues in Human Plasma

Determination and metabolism of dithiol chelating agents. VI. Isolation and identification of the mixed disulfides of meso-2,3-dimercaptosuccinic acid with L-cysteine in human urine.

Urinary excretion of meso‐2,3‐dimercaptosuccinic acid in human subjects

Gas-Chromatographic Method for the Halothane Metabolites, Trifluoroacetic Acid and Bromide, in Biological Fluids

Dimercaptan metal-binding agents influence the biotransformation of arsenite in the rabbit.