As a normal attribute of aerobic life, structural damage to organic compounds of a wide variety (DNA, proteins, carbohydrates and lipids) may occur as a consequence of oxidative reactions. Oxidative damage inflicted by reactive oxygen species has been called “oxidative stress”. Biological systems contain powerful enzymatic and nonenzymatic antioxidant systems, and oxidative stress denotes a shift in the prooxidant/antioxidant balance in favor of the former. Diverse biological processes such as inflammation, carcinogenesis, ageing, radiation damage and photobiological effects appear to involve reactive oxygen species. This field of research provides new perspectives in biochemical pharmacology, toxicology, radiation biochemistry as well as pathophysiology.

Biochemistry of Oxidative Stress

Glutathione (GSH) is a tripeptide, which has many biological roles including protection against reactive oxygen and nitrogen species. The primary goal of this paper is to characterize the principal mechanisms of the protective role of GSH against reactive species and electrophiles. The ancillary goals are to provide up-to-date knowledge of GSH biosynthesis, hydrolysis, and utilization; intracellular compartmentalization and interorgan transfer; elimination of endogenously produced toxicants; involvement in metal homeostasis; glutathione-related enzymes and their regulation; glutathionylation of sulfhydryls. Individual sections are devoted to the relationships between GSH homeostasis and pathologies as well as to developed research tools and pharmacological approaches to manipulating GSH levels. Special attention is paid to compounds mainly of a natural origin (phytochemicals) which affect GSH-related processes. The paper provides starting points for development of novel tools and provides a hypothesis for investigation of the physiology and biochemistry of glutathione with a focus on human and animal health.

https://downloads.hindawi.com/archive/2012/736837.pdf

Glutathione Homeostasis and Functions: Potential Targets forMedical Interventions

Molecular and cellular aspects of thiol-disulfide exchange.

Glutathione (GSH)b performs a variety of important physiological and metabolic functions in all mammalian cells, including the detoxification of free radicals, metals, and other electrophilic compounds. One important detoxification mechanism involves the binding of GSH to electrophilic chemicals and

Endogenous Glutathione Conjugates: Occurrence and Biological Functions

Rapid advances in redox systems biology are creating new opportunities to understand complexities of human disease and contributions of environmental exposures. New understanding of thiol–disulfide systems have occurred during the past decade as a consequence of the discoveries that thiol and disulfide systems are maintained in kinetically controlled steady states displaced from thermodynamic equilibrium, that a widely distributed family of NADPH oxidases produces oxidants that function in cell signaling and that a family of peroxiredoxins utilize thioredoxin as a reductant to complement the well-studied glutathione antioxidant system for peroxide elimination and redox regulation. This review focuses on thiol/disulfide redox state in biologic systems and the knowledge base available to support development of integrated redox systems biology models to better understand the function and dysfunction of thiol–disulfide redox systems. In particular, central principles have emerged concerning redox comp...

/pdf/thiol-disulfide-redox-states-in-signaling-and-sensing-2izklk3mip.pdf

Thiol/disulfide redox states in signaling and sensing

Addition of t-butyl hydroperoxide to isolated perfused rat liver leads to a decreased flux through pyruvate dehydrogenase, shown by a decreased 14CO2 release from [1-14C]pyruvate. The effect is observed at rates of infusion of t-butyl hydroperoxide exceeding 0.7 mumol per min per g liver in normal livers and at significantly lower rates in glutathione-depleted livers. The effect is absent in livers from Se-deficient rats in which the hepatic Se-dependent glutathione peroxidase activity is very low, indicating that reduction of t-butyl hydroperoxide by glutathione peroxidase is a necessary prerequisite for the inhibition. With isolated mitochondria, decreased 14CO2 release from [1-14C]pyruvate during t-butyl hydroperoxide metabolism correlates with decreased GSH and increased GSSG contents, respectively. The addition of various disulfide compounds, including GSSG, inhibits activity of the enzyme in mitochondrial extracts. In both mitochondria and perfused liver, t-butyl hydroperoxide-mediated decrease of pyruvate dehydrogenase flux is relieved by thiol reductants. The active (dephospho)form of pyruvate dehydrogenase as measured in freeze-stopped liver samples is actually increased from 46% to 72% during t-butyl hydroperoxide metabolism. The tissue levels of ATP and ADP and perfusate beta-hydroxybutyrate/acetoacetate ratio are not markedly perturbed by addition of the hydroperoxide (10 min). It is concluded that the decreased flux through pyruvate dehydrogenase during t-butyl hydroperoxide metabolism results from oxidation of critical thiol group(s) of the enzyme complex consequential to a decrease in mitochondrial GSH/GSSG.

Decreased flux through pyruvate dehydrogenase by thiol oxidation during t-butyl hydroperoxide metabolism in perfused rat liver.

The hepatic metabolism of an externally added hydroperoxide, t-butyl hydroperoxide, results in substantial decreases in CoASH and acetyl-CoA and a concomitant increase in CoA-disulfides. The principal CoA-disulfide which is formed under these conditions was identified as CoASSG, the mixed disulfide of coenzyme A and glutathione; CoASSCoA levels were unchanged. The perturbation in the coenzyme A system was absent when the hydroperoxide was infused into livers from rats maintained on a selenium-deficient diet. In these livers, Se-dependent glutathione peroxidase is lowered to less than 5% of control levels; the observed effects can be attributed to flux through Se-dependent GSH peroxidase.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1982.tb06911.x

Rise of coenzyme A-glutathione mixed disulfide during hydroperoxide metabolism in perfused rat liver.

Addition of nitrofurantoin to isolated perfused rat liver leads to an inhibition of 14CO2 production from [1-14C]pyruvate, 2-oxo-[1-14C]isocaproate and 2-oxo-[1-14C]isovalerate, indicating a decreased flux through the corresponding mitochondrial 2-oxo-acid dehydrogenases. This is in agreement with a decreased tissue level of the active (dephospho)form of pyruvate dehydrogenase in presence of nitrofurantoin. 2) Evidence is presented for an inhibition of the monocarboxylate translocator in the mitochondrial membrane during addition of nitrofurantoin by comparing the effects of alpha-cyanocinnamate as a transport inhibitor with those of nitrofurantoin. 3) It is concluded that nitrofurantoin-induced hepatocyte toxicity may include mitochondrial effects due to decreased oxo-acid dehydrogenase flux.

Denis Crane

Papers

Decreased flux through pyruvate dehydrogenase by thiol oxidation during t-butyl hydroperoxide metabolism in perfused rat liver.

Rise of coenzyme A-glutathione mixed disulfide during hydroperoxide metabolism in perfused rat liver.

Decrease of flux through pyruvate dehydrogenase and branched-chain 2-oxo-acid dehydrogenase by nitrofurantoin in perfused rat liver.