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This review examines the effects of neurotoxic electrophiles on selenium (Se) metabolism. Selenium-dependent enzymes depend on the unique and elite functions of selenocysteine (Sec), the 21st proteinogenic amino acid, to perform their biochemical roles. Humans possess 25 selenoprotein genes, ˜ half of which are enzymes (selenoenzymes) required for preventing, controlling, or reversing oxidative damage, while others participate in regulating calcium metabolism, thyroid hormone status, protein folding, cytoskeletal structure, Sec synthesis and Se transport. While selenoproteins are expressed in tissue dependent distributions and levels in all cells of all vertebrates, they are particularly important in brain development, health, and functions. As the most potent intracellular nucleophile, Sec is subject to binding by mercury (Hg) and other electron poor soft neurotoxic electrophiles. Epidemiological and environmental studies of the effects of exposures to methyl-Hg (CH3Hg+), elemental Hg (Hg°), and/or other metallic/organic neurotoxic soft electrophiles need to consider the concomitant effects of all members of this class of toxicants in relation to the Se status of their study populations. The contributions of individual electrophiles’ discrete and cooperative rates of Se sequestration need to be evaluated in relation to tissue Se reserves of the exposed populations to identify sensitive subgroups which may be at accentuated risk due to poor Se status. Additional study is required to examine possibilities of inherited, acquired, or degenerative neurological disorders of Se homeostasis that may influence vulnerability to soft electrophile exposures. Investigations of soft electrophile toxicity will be enhanced by considering the concomitant effects of combined exposures on tissue Se-availability in relation to pathological consequences during fetal development or in relation to etiologies of neurological disorders and neurodegenerative diseases. Since selenoenzymes are molecular “targets” of soft electrophiles, concomitant evaluation of aggregate exposures to these toxicants in relation to dietary Se intakes will assist regulatory agencies in their goals of improving and protecting public health.Neurotoxic soft electrophiles irreversibly inhibit brain selenoenzymes.Mercury and other soft electrophiles bind thiols to form suicide substrates.Soft electrophiles bind selenocysteine-the 21st genetically encoded amino acid.Electrophiles inhibit selenoenzymes that prevent and reverse oxidative damage.