Arsenic-induced oxidative stress and its reversibility |
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Authors: | Flora Swaran J S |
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Affiliation: | Division of Pharmacology & Toxicology, Defence Research and Development Establishment, Jhansi Road, Gwalior 474002, India |
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Abstract: | This review summarizes the literature describing the molecular mechanisms of arsenic-induced oxidative stress, its relevant biomarkers, and its relation to various diseases, including preventive and therapeutic strategies. Arsenic alters multiple cellular pathways including expression of growth factors, suppression of cell cycle checkpoint proteins, promotion of and resistance to apoptosis, inhibition of DNA repair, alterations in DNA methylation, decreased immunosurveillance, and increased oxidative stress, by disturbing the pro/antioxidant balance. These alterations play prominent roles in disease manifestation, such as carcinogenicity, genotoxicity, diabetes, cardiovascular and nervous systems disorders. The exact molecular and cellular mechanisms involved in arsenic toxicity are rather unrevealed. Arsenic alters cellular glutathione levels either by utilizing this electron donor for the conversion of pentavalent to trivalent arsenicals or directly binding with it or by oxidizing glutathione via arsenic-induced free radical generation. Arsenic forms oxygen-based radicals (OH•, O2•−) under physiological conditions by directly binding with critical thiols. As a carcinogen, it acts through epigenetic mechanisms rather than as a classical mutagen. The carcinogenic potential of arsenic may be attributed to activation of redox-sensitive transcription factors and other signaling pathways involving nuclear factor κB, activator protein-1, and p53. Modulation of cellular thiols for protection against reactive oxygen species has been used as a therapeutic strategy against arsenic. N-acetylcysteine, α-lipoic acid, vitamin E, quercetin, and a few herbal extracts show prophylactic activity against the majority of arsenic-mediated injuries in both in vitro and in vivo models. This review also updates the reader on recent advances in chelation therapy and newer therapeutic strategies suggested to treat arsenic-induced oxidative damage. |
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Keywords: | GSH, glutathione GSSG, glutathione disulfide NAC, N-acetylcysteine ROS, reactive oxygen species RNS, reactive nitrogen species O2&bull &minus , superoxide anion &bull OH, hydroxyl radical 1O2, singlet oxygen MMAV, monomethyl arsonate MMAIII, monomethyl arsonous ODD, oxidative DNA damage PDH, pyruvate dehydrogenase XO, xanthine oxidase ESR, electron spin resonance 8-OHdG, 8-hydroxy-2-deoxyguanosine ALAD, δ-aminolevulinic acid dehydratase GST, glutathione S-transferase TNFα, tumor necrosis factor α DMSA, meso-2,3-dimercaptosuccinic acid MiADMSA, monoisoamyl-DMSA MMP, mitochondria membrane potential SOD, superoxide dismutase GPx, glutathione peroxidase GR, glutathione reductase AST, aspartate aminotransaminase CAT, catalase CK-2, casein kinase 2 RTK, receptor tyrosine kinase NTK, nonreceptor tyrosine kinase MAPK, mitogen-activated protein kinase ERK, extracellular signal-regulated kinase JNK, c-jun N-terminal kinase PKC, protein kinase C CDK, cyclin-dependent kinase AP-1, activator protein 1 NF-κB, nuclear factor κB GADD45, growth arrest and DNA damage 45 LDL, low-density lipoprotein Nrf2, transcription factor NF-E2-related factor 2 |
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