BBA - General Subjects (v.1830, #5)
Editorial Board (i).
Cellular functions of glutathione by Christopher Horst Lillig; Carsten Berndt (3137-3138).
The fairytale of the GSSG/GSH redox potential by Leopold Flohé (3139-3142).
The term GSSG/GSH redox potential is frequently used to explain redox regulation and other biological processes.The relevance of the GSSG/GSH redox potential as driving force of biological processes is critically discussed. It is recalled that the concentration ratio of GSSG and GSH reflects little else than a steady state, which overwhelmingly results from fast enzymatic processes utilizing, degrading or regenerating GSH.A biological GSSG/GSH redox potential, as calculated by the Nernst equation, is a deduced electrochemical parameter based on direct measurements of GSH and GSSG that are often complicated by poorly substantiated assumptions. It is considered irrelevant to the steering of any biological process. GSH-utilizing enzymes depend on the concentration of GSH, not on [GSH]2, as is predicted by the Nernst equation, and are typically not affected by GSSG. Regulatory processes involving oxidants and GSH are considered to make use of mechanistic principles known for thiol peroxidases which catalyze the oxidation of hydroperoxides by GSH by means of an enzyme substitution mechanism involving only bimolecular reaction steps.The negligibly small rate constants of related spontaneous reactions as compared with enzyme-catalyzed ones underscore the superiority of kinetic parameters over electrochemical or thermodynamic ones for an in-depth understanding of GSH-dependent biological phenomena. At best, the GSSG/GSH potential might be useful as an analytical tool to disclose disturbances in redox metabolism. This article is part of a Special Issue entitled Cellular Functions of Glutathione.► The priority of kinetic over thermodynamic parameters in biology is demonstrated. ► Mislabeling of glutathione as an ‘antioxidant’ is discouraged. ► Enzyme catalysis rather than ΔG or ΔE determines metabolic and regulatory events.
Keywords: Nernst equation; GSSG/GSH redox potential; Redox regulation; Glutathione peroxidases; Peroxiredoxins;
Glutathione synthesis by Shelly C. Lu (3143-3153).
Glutathione (GSH) is present in all mammalian tissues as the most abundant non-protein thiol that defends against oxidative stress. GSH is also a key determinant of redox signaling, vital in detoxification of xenobiotics, and regulates cell proliferation, apoptosis, immune function, and fibrogenesis. Biosynthesis of GSH occurs in the cytosol in a tightly regulated manner. Key determinants of GSH synthesis are the availability of the sulfur amino acid precursor, cysteine, and the activity of the rate-limiting enzyme, glutamate cysteine ligase (GCL), which is composed of a catalytic (GCLC) and a modifier (GCLM) subunit. The second enzyme of GSH synthesis is GSH synthetase (GS).This review summarizes key functions of GSH and focuses on factors that regulate the biosynthesis of GSH, including pathological conditions where GSH synthesis is dysregulated.GCL subunits and GS are regulated at multiple levels and often in a coordinated manner. Key transcription factors that regulate the expression of these genes include NF-E2 related factor 2 (Nrf2) via the antioxidant response element (ARE), AP-1, and nuclear factor kappa B (NFκB). There is increasing evidence that dysregulation of GSH synthesis contributes to the pathogenesis of many pathological conditions. These include diabetes mellitus, pulmonary and liver fibrosis, alcoholic liver disease, cholestatic liver injury, endotoxemia and drug-resistant tumor cells.GSH is a key antioxidant that also modulates diverse cellular processes. A better understanding of how its synthesis is regulated and dysregulated in disease states may lead to improvement in the treatment of these disorders. This article is part of a Special Issue entitled Cellular functions of glutathione.► GSH regulates antioxidant defense, growth, death, immune function, and fibrogenesis. ► GSH is synthesized via two enzymatic steps that are regulated at multiple levels. ► GSH synthesis is dysregulated in multiple human diseases.
Keywords: GSH; Glutamate-cysteine ligase; GSH synthase; Nrf2; MafG; Antioxidant response element;
Glutathione transporters by Anand K. Bachhawat; Anil Thakur; Jaspreet Kaur; M. Zulkifli (3154-3164).
Glutathione (GSH) is synthesized in the cytoplasm but there is a requirement for glutathione not only in the cytoplasm, but in the other organelles and the extracellular milieu. GSH is also imported into the cytoplasm. The transports of glutathione across these different membranes in different systems have been biochemically demonstrated. However the molecular identity of the transporters has been established only in a few cases.An attempt has been made to present the current state of knowledge of glutathione transporters from different organisms as well as different organelles. These include the most well characterized transporters, the yeast high-affinity, high-specificity glutathione transporters involved in import into the cytoplasm, and the mammalian MRP proteins involved in low affinity glutathione efflux from the cytoplasm. Other glutathione transporters that have been described either with direct or indirect evidences are also discussed.The molecular identity of a few glutathione transporters has been unambiguously established but there is a need to identify the transporters of other systems and organelles. There is a lack of direct evidence establishing transport by suggested transporters in many cases. Studies with the high affinity transporters have led to important structure-function insights.An understanding of glutathione transporters is critical to our understanding of redox homeostasis in living cells. By presenting our current state of understanding and the gaps in our knowledge the review hopes to stimulate research in these fields. This article is part of a Special Issue entitled Cellular functions of glutathione.► Glutathione transporters described in different organisms and different organelles. ► Eukaryotic cells have multiple glutathione transporters. ► Glutathione transporters have evolved from different protein families. ► Low and high affinity transporters are described. ► Yeast high affinity transporters have facilitated structure function studies.
Keywords: Glutathione transporter; Hgt1p (high affinity glutathione transporter); OPT (oligopeptide transporter family); MRP (multi-drug resistance protein); GSH import; GSH efflux;
Protein glutathionylation in health and disease by Pietro Ghezzi (3165-3172).
It is now recognized that protein cysteines exist not only as free thiols or intramolecular disulfides, that help maintain the 3D structure of proteins, but can also undergo different types of oxidation, one of which is glutathionylation, or the formation of mixed disulfides with glutathione (GSH).We will discuss how proteins can undergo glutathionylation and how this can affect the protein characteristics/function. Glutathionylation is reversible and de-glutathionylation can be catalysed by protein thiol–disulfide oxidoreductases. Genetic modification of the expression of these enzymes, particularly glutaredoxin, using overexpression, knockout mice or siRNA, is becoming an important tool to study the role of protein glutathionylation. While in the past this post-translational modification was mainly known in the context of oxidative stress, measurement of glutathionylated proteins in patients is pointing out a potential importance if this modification in pathogenesis and could identify new biomarkers. We also wanted to point out the main findings in the role of glutathionylation in diseases and drug action.We identify two major open problems in the field, namely the complexity of the mechanisms responsible for glutathionylation and de-glutathionylation, as well as what makes a protein susceptible to glutathionylation.This review underlines the peculiarities of this post-translational modification and their biological role. This article is part of a Special Issue entitled Cellular functions of glutathione.► Protein cysteines can form mixed disulfides with glutathione. ► Glutathionylation is reversible and can be enzyme-catalysed. ► Glutathionylation can modify protein characteristics and functions. ► Glutathionylated proteins can be changed in disease conditions.
Keywords: Glutathionylation; Cysteinylation; Glutaredoxin; Thioredoxin; Sulfiredoxin; Inflammation;
S-Nitrosoglutathione by Katarzyna A. Broniowska; Anne R. Diers; Neil Hogg (3173-3181).
S-Nitrosoglutathione (GSNO) is the S-nitrosated derivative of glutathione and is thought to be a critical mediator of the down stream signaling effects of nitric oxide (NO). GSNO has also been implicated as a contributor to various disease states.This review focuses on the chemical nature of GSNO, its biological activities, the evidence that it is an endogenous mediator of NO action, and implications for therapeutic use.GSNO clearly exerts its cellular actions through both NO- and S-nitrosation-dependent mechanisms; however, the chemical and biological aspects of this compound should be placed in the context of S-nitrosation as a whole.GSNO is a central intermediate in formation and degradation of cellular S-nitrosothiols with potential therapeutic applications; thus, it remains an important molecule of study. This article is part of a Special Issue entitled Cellular functions of glutathione.► GSNO exerts its actions through nitric oxide- and S-nitrosation-dependent mechanisms. ► GSNO effects should be placed in the context of S-nitrosation as a whole. ► A role for GSNO in pathology will likely drive its development as a therapeutic agent.
Keywords: S-nitrosation; S-nitrosylation; Nitric oxide; Thiol;
Glutathione analogs in prokaryotes by Robert C. Fahey (3182-3198).
Oxygen is both essential and toxic to all forms of aerobic life and the chemical versatility and reactivity of thiols play a key role in both aspects. Cysteine thiol groups have key catalytic functions in enzymes but are readily damaged by reactive oxygen species (ROS). Low-molecular-weight thiols provide protective buffers against the hazards of ROS toxicity. Glutathione is the small protective thiol in nearly all eukaryotes but in prokaryotes the situation is far more complex.This review provides an introduction to the diversity of low-molecular-weight thiol protective systems in bacteria. The topics covered include the limitations of cysteine as a protector, the multiple origins and distribution of glutathione biosynthesis, mycothiol biosynthesis and function in Actinobacteria, recent discoveries involving bacillithiol found in Firmicutes, new insights on the biosynthesis and distribution of ergothioneine, and the potential protective roles played by coenzyme A and other thiols.Bacteria have evolved a diverse collection of low-molecular-weight protective thiols to deal with oxygen toxicity and environmental challenges. Our understanding of how many of these thiols are produced and utilized is still at an early stage.Extensive diversity existed among prokaryotes prior to evolution of the cyanobacteria and the development of an oxidizing atmosphere. Bacteria that managed to adapt to life under oxygen evolved, or acquired, the ability to produce a variety of small thiols for protection against the hazards of aerobic metabolism. Many pathogenic prokaryotes depend upon novel thiol protection systems that may provide targets for new antibacterial agents. This article is part of a Special Issue entitled Cellular functions of glutathione.► Biosynthesis of glutathione appears to have evolved several times in prokaryotes. ► Mycothiol is found in Actinobacteria and has functions similar to glutathione. ► Bacillithiol, a new thiol found in Firmicutes, has received only limited study. ► Ergothioneine and coenzyme A may have protective roles in some prokaryotes. ► The biochemistry of small thiols is largely unexplored in many prokaryotes.
Keywords: Low-molecular-weight thiols; Glutathione; Mycothiol; Bacillithiol; Ergothioneine; Coenzyme A;
Trypanothione: A unique bis-glutathionyl derivative in trypanosomatids by Bruno Manta; Marcelo Comini; Andrea Medeiros; Martín Hugo; Madia Trujillo; Rafael Radi (3199-3216).
Trypanosomatids are early-diverging eukaryotes devoid of the major disulfide reductases – glutathione reductase and thioredoxin reductase – that control thiol-redox homeostasis in most organisms. These protozoans have evolved a unique thiol-redox system centered on trypanothione, a bis-glutathionyl conjugate of spermidine. Notably, the trypanothione system is capable to sustain several cellular functions mediated by thiol-dependent (redox) processes.This review provides a summary of some historical and evolutionary aspects related to the discovery and appearance of trypanothione in trypanosomatids. It also addresses trypanothione's biosynthesis, physicochemical properties and reactivity towards biologically-relevant oxidants as well as its participation as a cofactor for metal binding. In addition, the role of the second most abundant thiol of trypanosomatids, glutathione, is revisited in light of the putative glutathione-dependent activities identified in these organisms.Based on biochemical and genome data, the occurrence of a thiol-redox system that is strictly dependent on trypanothione appears to be a feature unique to the order Kinetoplastida. The properties of trypanothione, a dithiol, are the basis for its unique reactivity towards a wide diversity of oxidized and/or electrophilic moieties in proteins and low molecular weight compounds from endogenous or exogenous sources. Novel functions have emerged for trypanothione as a potential cofactor in iron metabolism.The minimalist thiol-redox system, developed by trypanosomatids, is an example of metabolic fitness driven by the remarkable physicochemical properties of a glutathione derivative. From a pharmacological point of view, such specialization is the Achilles' heel of these ancient and deadly parasites. This article is part of a Special Issue entitled Cellular functions of glutathione.► Trypanosomes posses a unique thiol-redox system centered on trypanothione, a bis-glutathionyl conjugate of spermidine. ► Trypanothione system sustains cellular functions that in higher eukaryotes rely on glutathione or thioredoxin systems. ► Trypanothione-dependent redox-metabolism is the Achilles' heel of these ancient and deadly parasites.
Keywords: Trypanosome; Polyamine; Antioxidant; Free radical; Redox;
Glutathione catalysis and the reaction mechanisms of glutathione-dependent enzymes by Marcel Deponte (3217-3266).
Glutathione-dependent catalysis is a metabolic adaptation to chemical challenges encountered by all life forms. In the course of evolution, nature optimized numerous mechanisms to use glutathione as the most versatile nucleophile for the conversion of a plethora of sulfur-, oxygen- or carbon-containing electrophilic substances.This comprehensive review summarizes fundamental principles of glutathione catalysis and compares the structures and mechanisms of glutathione-dependent enzymes, including glutathione reductase, glutaredoxins, glutathione peroxidases, peroxiredoxins, glyoxalases 1 and 2, glutathione transferases and MAPEG. Moreover, open mechanistic questions, evolutionary aspects and the physiological relevance of glutathione catalysis are discussed for each enzyme family.It is surprising how little is known about many glutathione-dependent enzymes, how often reaction geometries and acid–base catalysts are neglected, and how many mechanistic puzzles remain unsolved despite almost a century of research. On the one hand, several enzyme families with non-related protein folds recognize the glutathione moiety of their substrates. On the other hand, the thioredoxin fold is often used for glutathione catalysis. Ancient as well as recent structural changes of this fold did not only significantly alter the reaction mechanism, but also resulted in completely different protein functions.Glutathione-dependent enzymes are excellent study objects for structure–function relationships and molecular evolution. Notably, in times of systems biology, the outcome of models on glutathione metabolism and redox regulation is more than questionable as long as fundamental enzyme properties are neither studied nor understood. Furthermore, several of the presented mechanisms could have implications for drug development. This article is part of a Special Issue entitled Cellular functions of glutathione.► Fundamental principles of glutathione catalysis are summarized. ► Mechanisms of enzymes with five non-related protein folds are compared. ► Evolutionary aspects and open mechanistic questions are discussed. ► The physiological relevance of glutathione catalysis is highlighted.
Keywords: Catalysis; Glutathione; Enzyme; Redox; Thiol; Electrophile;
Glutathione transferases, regulators of cellular metabolism and physiology by Philip G. Board; Deepthi Menon (3267-3288).
The cytosolic glutathione transferases (GSTs) comprise a super family of proteins that can be categorized into multiple classes with a mixture of highly specific and overlapping functions.The review covers the genetics, structure and function of the human cytosolic GSTs with particular attention to their emerging roles in cellular metabolism.All the catalytically active GSTs contribute to the glutathione conjugation or glutathione dependant-biotransformation of xenobiotics and many catalyze glutathione peroxidase or thiol transferase reactions. GSTs also catalyze glutathione dependent isomerization reactions required for the synthesis of several prostaglandins and steroid hormones and the catabolism of tyrosine. An increasing body of work has implicated several GSTs in the regulation of cell signaling pathways mediated by stress-activated kinases like Jun N-terminal kinase. In addition, some members of the cytosolic GST family have been shown to form ion channels in intracellular membranes and to modulate ryanodine receptor Ca2 + channels in skeletal and cardiac muscle.In addition to their well established roles in the conjugation and biotransformation of xenobiotics, GSTs have emerged as significant regulators of pathways determining cell proliferation and survival and as regulators of ryanodine receptors that are essential for muscle function. This article is part of a Special Issue entitled Cellular functions of glutathione.► Glutathione transferases are known for their capacity to conjugate xenobiotics. ► Glutathione transferases isomerize intermediates in steroid hormone synthesis. ► Zeta class glutathione transferases catalyze a required step in tyrosine catabolism. ► Several glutathione transferases regulate signaling pathways through JNK. ► Some members of the GST family form and modulate ion channels.
Keywords: Glutathione transferase;
Glutathione peroxidases by Regina Brigelius-Flohé; Matilde Maiorino (3289-3303).
With increasing evidence that hydroperoxides are not only toxic but rather exert essential physiological functions, also hydroperoxide removing enzymes have to be re-viewed. In mammals, the peroxidases inter alia comprise the 8 glutathione peroxidases (GPx1–GPx8) so far identified.Since GPxs have recently been reviewed under various aspects, we here focus on novel findings considering their diverse physiological roles exceeding an antioxidant activity.GPxs are involved in balancing the H2O2 homeostasis in signalling cascades, e.g. in the insulin signalling pathway by GPx1; GPx2 plays a dual role in carcinogenesis depending on the mode of initiation and cancer stage; GPx3 is membrane associated possibly explaining a peroxidatic function despite low plasma concentrations of GSH; GPx4 has novel roles in the regulation of apoptosis and, together with GPx5, in male fertility. Functions of GPx6 are still unknown, and the proposed involvement of GPx7 and GPx8 in protein folding awaits elucidation.Collectively, selenium-containing GPxs (GPx1–4 and 6) as well as their non-selenium congeners (GPx5, 7 and 8) became key players in important biological contexts far beyond the detoxification of hydroperoxides. This article is part of a Special Issue entitled Cellular functions of glutathione.► Novel functions of GPx1–8 regarding the essential physiological functions of ROS ► Balancing levels of H2O2 in, e.g., insulin signalling by GPx1 ► The role of GPx2 in cancer depends on the mode of initiation and cancer stage ► Specific roles of GPx4 in apoptosis and together with GPx5 in male fertility ► Downregulation as well as overexpression of GPxs can have harmful effects.
Keywords: Glutathione peroxidases; Redox regulation; Hydroperoxide balance; Cancer; Inflammation; Spermatogenesis;
Nuclear glutathione by José Luis García-Giménez; Jelena Markovic; Francisco Dasí; Guillaume Queval; Daniel Schnaubelt; Christine H. Foyer; Federico V. Pallardó (3304-3316).
Glutathione (GSH) is a linchpin of cellular defences in plants and animals with physiologically-important roles in the protection of cells from biotic and abiotic stresses. Moreover, glutathione participates in numerous metabolic and cell signalling processes including protein synthesis and amino acid transport, DNA repair and the control of cell division and cell suicide programmes. While it is has long been appreciated that cellular glutathione homeostasis is regulated by factors such as synthesis, degradation, transport, and redox turnover, relatively little attention has been paid to the influence of the intracellular partitioning on glutathione and its implications for the regulation of cell functions and signalling. We focus here on the functions of glutathione in the nucleus, particularly in relation to physiological processes such as the cell cycle and cell death. The sequestration of GSH in the nucleus of proliferating animal and plant cells suggests that common redox mechanisms exist for DNA regulation in G1 and mitosis in all eukaryotes. We propose that glutathione acts as “redox sensor” at the onset of DNA synthesis with roles in maintaining the nuclear architecture by providing the appropriate redox environment for the DNA replication and safeguarding DNA integrity. In addition, nuclear GSH may be involved in epigenetic phenomena and in the control of nuclear protein degradation by nuclear proteasome. Moreover, by increasing the nuclear GSH pool and reducing disulfide bonds on nuclear proteins at the onset of cell proliferation, an appropriate redox environment is generated for the stimulation of chromatin decompaction. This article is part of a Special Issue entitled Cellular functions of glutathione.► Nuclear glutathione is essential for cell proliferation in mammalian and plant cells. ► Nuclear glutathione regulates transcription factors. ► Epigenetic marks in histones are associated with changes in nuclear GSH.
Keywords: Nucleus; Glutathione; Chromatin; Poly(ADP-ribosyl)ation; Transcription factors; Cell cycle;
Mitochondrial glutathione: Features, regulation and role in disease by Montserrat Marí; Albert Morales; Anna Colell; Carmen García-Ruiz; Neil Kaplowitz; José C. Fernández-Checa (3317-3328).
Mitochondria are the powerhouse of mammalian cells and the main source of reactive oxygen species (ROS) associated with oxygen consumption. In addition, they also play a strategic role in controlling the fate of cells through regulation of death pathways. Mitochondrial ROS production fulfills a signaling role through regulation of redox pathways, but also contributes to mitochondrial damage in a number of pathological states.Mitochondria are exposed to the constant generation of oxidant species, and yet the organelle remains functional due to the existence of an armamentarium of antioxidant defense systems aimed to repair oxidative damage, of which mitochondrial glutathione (mGSH) is of particular relevance. Thus, the aim of the review is to cover the regulation of mGSH and its role in disease.Cumulating evidence over recent years has demonstrated the essential role for mGSH in mitochondrial physiology and disease. Despite its high concentration in the mitochondrial matrix, mitochondria lack the enzymes to synthesize GSH de novo, so that mGSH originates from cytosolic GSH via transport through specific mitochondrial carriers, which exhibit sensitivity to membrane dynamics. Depletion of mGSH sensitizes cells to stimuli leading to oxidative stress such as TNF, hypoxia or amyloid β-peptide, thereby contributing to disease pathogenesis.Understanding the regulation of mGSH may provide novel insights to disease pathogenesis and toxicity and the opportunity to design therapeutic targets of intervention in cell death susceptibility and disease. This article is part of a Special Issue entitled Cellular functions of glutathione.► Role of mitochondrial GSH in oxidative stress and mitochondrial physiology. ► Description and features of mitochondrial GSH transport carriers. ► Role and mechanisms of mitochondrial GSH in cell death pathways. ► Contribution of mitochondrial GSH in neurodegeneration and liver diseases.
Keywords: Mitochondrion; Cholesterol; Steatohepatitis; Neurodegeneration; GSH;
Glutathione and infection by Devin Morris; Melissa Khurasany; Thien Nguyen; John Kim; Frederick Guilford; Rucha Mehta; Dennis Gray; Beatrice Saviola; Vishwanath Venketaraman (3329-3349).
The tripeptide γ-glutamylcysteinylglycine or glutathione (GSH) has demonstrated protective abilities against the detrimental effects of oxidative stress within the human body, as well as protection against infection by exogenous microbial organisms.In this review we describe how GSH works to modulate the behavior of many cells including the cells of the immune system, augmenting the innate and the adaptive immunity as well as conferring protection against microbial, viral and parasitic infections. This article unveils the direct antimicrobial effects of GSH in controlling Mycobacterium tuberculosis (M. tb) infection within macrophages. In addition, we summarize the effects of GSH in enhancing the functional activity of various immune cells such as natural killer (NK) cells and T cells resulting in inhibition in the growth of M. tb inside monocytes and macrophages. Most importantly we correlate the decreased GSH levels previously observed in individuals with pulmonary tuberculosis (TB) with an increase in the levels of pro-inflammatory cytokines which aid in the growth of M. tb. In conclusion, this review provides detailed information on the protective integral effects of GSH along with its therapeutic effects as they relate to the human immune system and health.It is important to note that the increases in the levels of pro-inflammatory cytokines are not only detrimental to the host due to the sequel that follow such as fever and cachexia, but also due to the alteration in the functions of immune cells. The additional protective effects of GSH are evident after sequel that follows the depletion of this antioxidant. This is evident in a condition such as Cystic Fibrosis (CF) where an increased oxidant burden inhibits the clearance of the affecting organism and results in oxidant-induced anti-protease inhibition. GSH has a similar protective effect in protozoans as it does in human cells. Thus GSH is integral to the survival of some of the protozoans because some protozoans utilize the compound trypanothione [T(SH)2] as their main antioxidant. T(SH)2 in turn requires GSH for its production. Hence a decrease in the levels of GSH (by a known inhibitor such as buthionine sulfoximine [BSO] can have adverse effects of the protozoan parasites. This article is part of a Special Issue entitled Cellular functions of glutathione.► Antimycobacterial and immune enhancing effects of glutathione. ► Glutathione deficiency in HIV, tuberculosis, diabetes and cystic fibrosis. ► Glutathione supplementation to prevent tuberculosis in susceptible individuals.
Keywords: Glutathione; Mycobacterium tuberculosis; HIV; AIDS; Innate immunity; Adaptive immunity; Macrophage; NK cell; T cell;
Glutathione and glutathione analogues; Therapeutic potentials by Jian Hui Wu; Gerald Batist (3350-3353).
Glutathione (GSH) and related enzymes are critical to cell protection from toxins, both endogenous and environmental, including a number of anti-cancer cytotoxic agents.Enhancing GSH and associated enzymes represents a longtime and persistent aim in the search for cytoprotective strategies against cancer, neurologic degeneration, pulmonary and inflammatory conditions, as well as cardiovascular ailments. The challenge is to identify effective GSH analogues or precursors that generate mimic molecules with glutathione's cellular protective effects. This review will provide an update on these efforts. Much effort has also been directed at depleting cellular GSH and related cytoprotective effects, in order to sensitize established tumors to the cytotoxic effects of anti-cancer agents. Efforts to deplete GSH have been limited by the challenge of selectivity doing so in tumor and not in normal tissue so as to avoid enhancing the toxicity of anti-cancer drugs. This review will also provide an update of efforts at overcoming the challenge of targeting the desired GSH depletion to tumor cells.This chapter provides a brief background and update of progress in the development and use of GSH analogues in the therapeutic setting, including the pharmacological aspects of these compounds.This is an area of enormous research activity, and major advances promise the advent of novel therapeutic opportunities in the near future.This article is part of a Special Issue entitled Cellular functions of glutathione.► GSH analogues and other strategies to enhance detox capacity ► Experimental and clinical works on this ► Clinical implications for GSH modulation
Keywords: Glutathione; Cytoprotection; Chemosensitivity;