The Pharmacology and Therapeutic Utility of Sodium Hydroselenide.

Metabolically active gasotransmitters (nitric oxide, carbon monoxide and hydrogen sulfide) are important signalling molecules that show therapeutic utility in oxidative pathologies. The reduced form of selenium, hydrogen selenide (HSe-/H2Se), shares some characteristics with these molecules. The simple selenide salt, sodium hydroselenide (NaHSe) showed significant metabolic activity, dose-dependently decreasing ex vivo O2 consumption (rat soleus muscle, liver) and transiently inhibiting mitochondrial cytochrome C oxidase (liver, heart). Pharmacological manipulation of selenoprotein expression in HepG2 human hepatocytes revealed that the oxidation status of selenium impacts on protein expression; reduced selenide (NaHSe) increased, whereas (oxidized) sodium selenite decreased the abundance of two ubiquitous selenoproteins. An inhibitor of endogenous sulfide production (DL-propargylglycine; PAG) also reduced selenoprotein expression; this was reversed by exogenous NaHSe, but not sodium hydrosulfide (NaHS). NaHSe also conferred cytoprotection against an oxidative challenge (H2O2), and this was associated with an increase in mitochondrial membrane potential. Anesthetized Wistar rats receiving intravenous NaHSe exhibited significant bradycardia, metabolic acidosis and hyperlactataemia. In summary, NaHSe modulates metabolism by inhibition of cytochrome C oxidase. Modification of selenoprotein expression revealed the importance of oxidation status of selenium therapies, with implications for current clinical practice. The utility of NaHSe as a research tool and putative therapeutic is discussed.

Selenium and hydrogen selenide: essential micronutrient and the fourth gasotransmitter?

Selenium (Se) is an essential micronutrient required by organisms of diverse lineage. Dietary Se is converted to hydrogen selenide either enzymatically or by endogenous antioxidant proteins. This convergent biochemical step crucially underlies the subsequent biological activity of Se and argues for inclusion of hydrogen selenide as the fourth endogenous gasotransmitter alongside nitric oxide, carbon monoxide and hydrogen sulfide.Endogenously generated hydrogen selenide is incorporated into numerous 'selenoprotein' oxidoreductase enzymes, essential for maintaining redox-status homeostasis in health and disease. Direct effects of endogenous hydrogen selenide on cellular and molecular targets are currently unknown. Given exogenously, hydrogen selenide acts as a modulator of metabolism via transient inhibition of mitochondrial cytochrome C oxidase. Here we provide an overview of Se biology, its impact on several physiological systems (immune, endocrine, cardiovascular and metabolic) and its utility as a supplement in acute and critical illness states. We further explore the evidence base supporting its role as the fourth gasotransmitter and propose a strategic case towards generation of novel selenomimetic therapeutics.