Glutathione dysregulation and the etiology and progression of human diseases

Abstract

Glutathione (GSH) plays an important role in a multitude of cellular processes, including cell differentiation, proliferation, and apoptosis, and as a result, disturbances in GSH homeostasis are implicated in the etiology and/or progression of a number of human diseases, including cancer, diseases of aging, cystic fibrosis, and cardiovascular, inflammatory, immune, metabolic, and neurodegenerative diseases. Owing to the pleiotropic effects of GSH on cell functions, it has been quite difficult to define the role of GSH in the onset and/or the expression of human diseases, although significant progress is being made. GSH levels, turnover rates, and/or oxidation state can be compromised by inherited or acquired defects in the enzymes, transporters, signaling molecules, or transcription factors that are involved in its homeostasis, or from exposure to reactive chemicals or metabolic intermediates. GSH deficiency or a decrease in the GSH/glutathione disulfide ratio manifests itself largely through an increased susceptibility to oxidative stress, and the resulting damage is thought to be involved in diseases, such as cancer, Parkinson's disease, and Alzheimer's disease. In addition, imbalances in GSH levels affect immune system function, and are thought to play a role in the aging process. Just as low intracellular GSH levels decrease cellular antioxidant capacity, elevated GSH levels generally increase antioxidant capacity and resistance to oxidative stress, and this is observed in many cancer cells. The higher GSH levels in some tumor cells are also typically associated with higher levels of GSH-related enzymes and transporters. Although neither the mechanism nor the implications of these changes are well defined, the high GSH content makes cancer cells chemoresistant, which is a major factor that limits drug treatment. The present report highlights and integrates the growing connections between imbalances in GSH homeostasis and a multitude of human diseases.

Figure 1. Major pathways of glutathione homeostasis in mammalian cells

(A) GSH is synthesized in the cell cytosol from its precursor amino acids, glutamate, cysteine and glycine. Within the cell, it exists mainly (>98%) in the thiol-reduced form (GSH), but some is also present as glutathione disulfide (GSSG), and as glutathione conjugates (GS-R). (B) After its synthesis, some of the GSH is delivered into specific intracellular compartments, including mitochondria and endoplasmic reticulum, but much of the GSH is delivered to extracellular spaces, including blood plasma, exocrine secretions, lung lining fluid, and cerebrospinal fluid. In polarized cells, transport of GSH and its conjugates across the apical membrane is mediated largely by MRP2, whereas MRP1 and rat Oatp1 may contribute to GSH efflux across the basolateral plasma membrane into blood plasma, although the specific proteins that mediate GSH export and intracellular compartmentation remain poorly defined. (C) In contrast to GSH synthesis, which occurs intracellularly, GSH degradation occurs exclusively in the extracellular space, and only on the surface of cells that express the ectoenzyme γ-glutamyl transpeptidase. This enzyme is found on the apical membrane of many epithelial cells, but is also abundant at other key sites, including the kidney basolateral compartment. Once GSH and GSH-containing compounds are exported from cells, there are efficient intra- and inter-organ cycles of glutathione degradation and utilization consisting of: (a) extensive catabolism within apical spaces (e.g., bile and renal tubular fluid), as well as within sinusoidal compartments of some species; (b) cellular re-uptake of some of the breakdown products; and (c) intracellular utilization of these breakdown products, or conversion of cysteine S-conjugates (Cys-SR) to mercapturic acids, i.e., N-acetylcysteine S-conjugates (N-acetyl-Cys-SR). As illustrated in this panel, catabolism of glutathione S-conjugates (GS-R) leads to the formation of cysteine S-conjugates (Cys-SR). Cys-SRs are transported back into cells, where they may be substrates for the N-acetyltransferases, to generate N-acetyl-Cys-SRs, or mercapturic acids. Mercapturic acids are exported from cells for eventual elimination in urine or feces, but the transport mechanisms are not clearly defined. Note that γ-glutamyl transpeptidase can catalyze either hydrolyses reactions, to release free L-Glu, or transpeptidation reactions, to lead to the formation of γ-Glu bound to either amino acids or peptides (γ-Glu-AA). These γ-Glu-AAs can be transported back into cells, where they are substrates for the enzyme γ-glutamyl cyclotransferase: this enzyme generates 5-oxoproline and releases the amino acid or peptide that is bound to L-Glu. 5-Oxoproline is converted to L-Glu by the ATP-requiring enzyme 5-oxoprolinase. (D) GSH is a cofactor, coenzyme, and/or substrate for a number of enzymes, and can participate in a number of redox and conjugation reactions. Notably GSH can react with many electrophilic chemicals to generate glutathione S-conjugates (GS-R). Although conjugation reactions can occur spontaneously, these reactions are often catalyzed by the glutathione S-transferases (GST). GSH also facilitates the reduction of oxidants via glutathione peroxidases (GPX), and is involved in maintaining the redox state of protein thiols via the enzymes glutaredoxins (GRX), thioredoxins (TRX), and peroxiredoxins (PRX).

Figure 1. Major pathways of glutathione homeostasis in mammalian cells

(A) GSH is synthesized in the cell cytosol from its precursor amino acids, glutamate, cysteine and glycine. Within the cell, it exists mainly (>98%) in the thiol-reduced form (GSH), but some is also present as glutathione disulfide (GSSG), and as glutathione conjugates (GS-R). (B) After its synthesis, some of the GSH is delivered into specific intracellular compartments, including mitochondria and endoplasmic reticulum, but much of the GSH is delivered to extracellular spaces, including blood plasma, exocrine secretions, lung lining fluid, and cerebrospinal fluid. In polarized cells, transport of GSH and its conjugates across the apical membrane is mediated largely by MRP2, whereas MRP1 and rat Oatp1 may contribute to GSH efflux across the basolateral plasma membrane into blood plasma, although the specific proteins that mediate GSH export and intracellular compartmentation remain poorly defined. (C) In contrast to GSH synthesis, which occurs intracellularly, GSH degradation occurs exclusively in the extracellular space, and only on the surface of cells that express the ectoenzyme γ-glutamyl transpeptidase. This enzyme is found on the apical membrane of many epithelial cells, but is also abundant at other key sites, including the kidney basolateral compartment. Once GSH and GSH-containing compounds are exported from cells, there are efficient intra- and inter-organ cycles of glutathione degradation and utilization consisting of: (a) extensive catabolism within apical spaces (e.g., bile and renal tubular fluid), as well as within sinusoidal compartments of some species; (b) cellular re-uptake of some of the breakdown products; and (c) intracellular utilization of these breakdown products, or conversion of cysteine S-conjugates (Cys-SR) to mercapturic acids, i.e., N-acetylcysteine S-conjugates (N-acetyl-Cys-SR). As illustrated in this panel, catabolism of glutathione S-conjugates (GS-R) leads to the formation of cysteine S-conjugates (Cys-SR). Cys-SRs are transported back into cells, where they may be substrates for the N-acetyltransferases, to generate N-acetyl-Cys-SRs, or mercapturic acids. Mercapturic acids are exported from cells for eventual elimination in urine or feces, but the transport mechanisms are not clearly defined. Note that γ-glutamyl transpeptidase can catalyze either hydrolyses reactions, to release free L-Glu, or transpeptidation reactions, to lead to the formation of γ-Glu bound to either amino acids or peptides (γ-Glu-AA). These γ-Glu-AAs can be transported back into cells, where they are substrates for the enzyme γ-glutamyl cyclotransferase: this enzyme generates 5-oxoproline and releases the amino acid or peptide that is bound to L-Glu. 5-Oxoproline is converted to L-Glu by the ATP-requiring enzyme 5-oxoprolinase. (D) GSH is a cofactor, coenzyme, and/or substrate for a number of enzymes, and can participate in a number of redox and conjugation reactions. Notably GSH can react with many electrophilic chemicals to generate glutathione S-conjugates (GS-R). Although conjugation reactions can occur spontaneously, these reactions are often catalyzed by the glutathione S-transferases (GST). GSH also facilitates the reduction of oxidants via glutathione peroxidases (GPX), and is involved in maintaining the redox state of protein thiols via the enzymes glutaredoxins (GRX), thioredoxins (TRX), and peroxiredoxins (PRX).

Figure 1. Major pathways of glutathione homeostasis in mammalian cells

(A) GSH is synthesized in the cell cytosol from its precursor amino acids, glutamate, cysteine and glycine. Within the cell, it exists mainly (>98%) in the thiol-reduced form (GSH), but some is also present as glutathione disulfide (GSSG), and as glutathione conjugates (GS-R). (B) After its synthesis, some of the GSH is delivered into specific intracellular compartments, including mitochondria and endoplasmic reticulum, but much of the GSH is delivered to extracellular spaces, including blood plasma, exocrine secretions, lung lining fluid, and cerebrospinal fluid. In polarized cells, transport of GSH and its conjugates across the apical membrane is mediated largely by MRP2, whereas MRP1 and rat Oatp1 may contribute to GSH efflux across the basolateral plasma membrane into blood plasma, although the specific proteins that mediate GSH export and intracellular compartmentation remain poorly defined. (C) In contrast to GSH synthesis, which occurs intracellularly, GSH degradation occurs exclusively in the extracellular space, and only on the surface of cells that express the ectoenzyme γ-glutamyl transpeptidase. This enzyme is found on the apical membrane of many epithelial cells, but is also abundant at other key sites, including the kidney basolateral compartment. Once GSH and GSH-containing compounds are exported from cells, there are efficient intra- and inter-organ cycles of glutathione degradation and utilization consisting of: (a) extensive catabolism within apical spaces (e.g., bile and renal tubular fluid), as well as within sinusoidal compartments of some species; (b) cellular re-uptake of some of the breakdown products; and (c) intracellular utilization of these breakdown products, or conversion of cysteine S-conjugates (Cys-SR) to mercapturic acids, i.e., N-acetylcysteine S-conjugates (N-acetyl-Cys-SR). As illustrated in this panel, catabolism of glutathione S-conjugates (GS-R) leads to the formation of cysteine S-conjugates (Cys-SR). Cys-SRs are transported back into cells, where they may be substrates for the N-acetyltransferases, to generate N-acetyl-Cys-SRs, or mercapturic acids. Mercapturic acids are exported from cells for eventual elimination in urine or feces, but the transport mechanisms are not clearly defined. Note that γ-glutamyl transpeptidase can catalyze either hydrolyses reactions, to release free L-Glu, or transpeptidation reactions, to lead to the formation of γ-Glu bound to either amino acids or peptides (γ-Glu-AA). These γ-Glu-AAs can be transported back into cells, where they are substrates for the enzyme γ-glutamyl cyclotransferase: this enzyme generates 5-oxoproline and releases the amino acid or peptide that is bound to L-Glu. 5-Oxoproline is converted to L-Glu by the ATP-requiring enzyme 5-oxoprolinase. (D) GSH is a cofactor, coenzyme, and/or substrate for a number of enzymes, and can participate in a number of redox and conjugation reactions. Notably GSH can react with many electrophilic chemicals to generate glutathione S-conjugates (GS-R). Although conjugation reactions can occur spontaneously, these reactions are often catalyzed by the glutathione S-transferases (GST). GSH also facilitates the reduction of oxidants via glutathione peroxidases (GPX), and is involved in maintaining the redox state of protein thiols via the enzymes glutaredoxins (GRX), thioredoxins (TRX), and peroxiredoxins (PRX).

Figure 1. Major pathways of glutathione homeostasis in mammalian cells

(A) GSH is synthesized in the cell cytosol from its precursor amino acids, glutamate, cysteine and glycine. Within the cell, it exists mainly (>98%) in the thiol-reduced form (GSH), but some is also present as glutathione disulfide (GSSG), and as glutathione conjugates (GS-R). (B) After its synthesis, some of the GSH is delivered into specific intracellular compartments, including mitochondria and endoplasmic reticulum, but much of the GSH is delivered to extracellular spaces, including blood plasma, exocrine secretions, lung lining fluid, and cerebrospinal fluid. In polarized cells, transport of GSH and its conjugates across the apical membrane is mediated largely by MRP2, whereas MRP1 and rat Oatp1 may contribute to GSH efflux across the basolateral plasma membrane into blood plasma, although the specific proteins that mediate GSH export and intracellular compartmentation remain poorly defined. (C) In contrast to GSH synthesis, which occurs intracellularly, GSH degradation occurs exclusively in the extracellular space, and only on the surface of cells that express the ectoenzyme γ-glutamyl transpeptidase. This enzyme is found on the apical membrane of many epithelial cells, but is also abundant at other key sites, including the kidney basolateral compartment. Once GSH and GSH-containing compounds are exported from cells, there are efficient intra- and inter-organ cycles of glutathione degradation and utilization consisting of: (a) extensive catabolism within apical spaces (e.g., bile and renal tubular fluid), as well as within sinusoidal compartments of some species; (b) cellular re-uptake of some of the breakdown products; and (c) intracellular utilization of these breakdown products, or conversion of cysteine S-conjugates (Cys-SR) to mercapturic acids, i.e., N-acetylcysteine S-conjugates (N-acetyl-Cys-SR). As illustrated in this panel, catabolism of glutathione S-conjugates (GS-R) leads to the formation of cysteine S-conjugates (Cys-SR). Cys-SRs are transported back into cells, where they may be substrates for the N-acetyltransferases, to generate N-acetyl-Cys-SRs, or mercapturic acids. Mercapturic acids are exported from cells for eventual elimination in urine or feces, but the transport mechanisms are not clearly defined. Note that γ-glutamyl transpeptidase can catalyze either hydrolyses reactions, to release free L-Glu, or transpeptidation reactions, to lead to the formation of γ-Glu bound to either amino acids or peptides (γ-Glu-AA). These γ-Glu-AAs can be transported back into cells, where they are substrates for the enzyme γ-glutamyl cyclotransferase: this enzyme generates 5-oxoproline and releases the amino acid or peptide that is bound to L-Glu. 5-Oxoproline is converted to L-Glu by the ATP-requiring enzyme 5-oxoprolinase. (D) GSH is a cofactor, coenzyme, and/or substrate for a number of enzymes, and can participate in a number of redox and conjugation reactions. Notably GSH can react with many electrophilic chemicals to generate glutathione S-conjugates (GS-R). Although conjugation reactions can occur spontaneously, these reactions are often catalyzed by the glutathione S-transferases (GST). GSH also facilitates the reduction of oxidants via glutathione peroxidases (GPX), and is involved in maintaining the redox state of protein thiols via the enzymes glutaredoxins (GRX), thioredoxins (TRX), and peroxiredoxins (PRX).