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Journal ArticleDOI

Biologic and pharmacologic regulation of mammalian glutathione synthesis.

01 Nov 1999-Free Radical Biology and Medicine (Free Radic Biol Med)-Vol. 27, Iss: 9, pp 922-935
TL;DR: Because GSH plays a critical role in cellular defenses against electrophiles, oxidative stress and nitrosating species, pharmacologic manipulation of GSH synthesis has received much attention.
About: This article is published in Free Radical Biology and Medicine.The article was published on 1999-11-01. It has received 1120 citations till now. The article focuses on the topics: Glutathione & Buthionine sulfoximine.
Citations
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Journal ArticleDOI
TL;DR: Estimates can be used to more fully understand the redox biochemistry that results from oxidative stress, which hopefully will provide a rationale and understanding of the cellular mechanisms associated with cell growth and development, signaling, and reductive or oxidative stress.

4,274 citations


Cites background from "Biologic and pharmacologic regulati..."

  • ...A recent forum on glutathione in Free Radical Biology and Medicineprovides more information on GSH and its cellular functions [59], regulation of GSH synthesis [60], gene expression and thiol redox state [52], BCL-2 and GSH [61], glutathione peroxidases [62], thiol-dependent hydroperoxide metabolism in parasites [63], and export pumps for GSH S-conjugates [64]....

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Journal ArticleDOI
TL;DR: Animal and human studies demonstrate that adequate protein nutrition is crucial for the maintenance of GSH homeostasis, and compelling evidence shows that GSH synthesis is regulated primarily by gamma-glutamylcysteine synthetase activity, cysteine availability, and GSH feedback inhibition.
Abstract: Glutathione (gamma-glutamyl-cysteinyl-glycine; GSH) is the most abundant low-molecular-weight thiol, and GSH/glutathione disulfide is the major redox couple in animal cells. The synthesis of GSH from glutamate, cysteine, and glycine is catalyzed sequentially by two cytosolic enzymes, gamma-glutamylcysteine synthetase and GSH synthetase. Compelling evidence shows that GSH synthesis is regulated primarily by gamma-glutamylcysteine synthetase activity, cysteine availability, and GSH feedback inhibition. Animal and human studies demonstrate that adequate protein nutrition is crucial for the maintenance of GSH homeostasis. In addition, enteral or parenteral cystine, methionine, N-acetyl-cysteine, and L-2-oxothiazolidine-4-carboxylate are effective precursors of cysteine for tissue GSH synthesis. Glutathione plays important roles in antioxidant defense, nutrient metabolism, and regulation of cellular events (including gene expression, DNA and protein synthesis, cell proliferation and apoptosis, signal transduction, cytokine production and immune response, and protein glutathionylation). Glutathione deficiency contributes to oxidative stress, which plays a key role in aging and the pathogenesis of many diseases (including kwashiorkor, seizure, Alzheimer's disease, Parkinson's disease, liver disease, cystic fibrosis, sickle cell anemia, HIV, AIDS, cancer, heart attack, stroke, and diabetes). New knowledge of the nutritional regulation of GSH metabolism is critical for the development of effective strategies to improve health and to treat these diseases.

3,096 citations

Journal ArticleDOI
TL;DR: Cellular adaptations in prefrontal glutamatergic innervation of the accumbens promote the compulsive character of drug seeking in addicts by decreasing the value of natural rewards, diminishing cognitive control (choice), and enhancing glutamatorgic drive in response to drug-associated stimuli.
Abstract: Objective: A primary behavioral pathology in drug addiction is the overpowering motivational strength and decreased ability to control the desire to obtain drugs. In this review the authors explore how advances in neurobiology are approaching an understanding of the cellular and circuitry underpinnings of addiction, and they describe the novel pharmacotherapeutic targets emerging from this understanding. Method: Findings from neuroimaging of addicts are integrated with cellular studies in animal models of drug seeking.

2,496 citations


Cites background from "Biologic and pharmacologic regulati..."

  • ...Procysteine drugs such as N-acetylcysteine have been used clinically to stimulate cystineglutamate exchange and restore glutathione following acetaminophen overdose (107)....

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Journal ArticleDOI
09 Apr 2009-Nature
TL;DR: It is shown that normal mammary epithelial stem cells contain lower concentrations of ROS than their more mature progeny cells, and subsets of CSCs in some tumours contain lower ROS levels and enhanced ROS defences compared to their non-tumorigenic progeny, which may contribute to tumour radioresistance.
Abstract: The metabolism of oxygen, although central to life, produces reactive oxygen species (ROS) that have been implicated in processes as diverse as cancer, cardiovascular disease and ageing. It has recently been shown that central nervous system stem cells and haematopoietic stem cells and early progenitors contain lower levels of ROS than their more mature progeny, and that these differences are critical for maintaining stem cell function. We proposed that epithelial tissue stem cells and their cancer stem cell (CSC) counterparts may also share this property. Here we show that normal mammary epithelial stem cells contain lower concentrations of ROS than their more mature progeny cells. Notably, subsets of CSCs in some human and murine breast tumours contain lower ROS levels than corresponding non-tumorigenic cells (NTCs). Consistent with ROS being critical mediators of ionizing-radiation-induced cell killing, CSCs in these tumours develop less DNA damage and are preferentially spared after irradiation compared to NTCs. Lower ROS levels in CSCs are associated with increased expression of free radical scavenging systems. Pharmacological depletion of ROS scavengers in CSCs markedly decreases their clonogenicity and results in radiosensitization. These results indicate that, similar to normal tissue stem cells, subsets of CSCs in some tumours contain lower ROS levels and enhanced ROS defences compared to their non-tumorigenic progeny, which may contribute to tumour radioresistance.

2,261 citations

Journal ArticleDOI
TL;DR: This article serves as introduction to the FRBM Forum on glutathione and emphasizes cellular functions: What is GSH?

1,607 citations

References
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Book
01 Jan 1972
TL;DR: The metabolic basis of inherited disease, the metabolic basis for inherited disease as mentioned in this paper, The metabolic basis in inherited disease and inherited diseases, and inherited disease diagnosis and management, in the context of inherited diseases
Abstract: The metabolic basis of inherited disease , The metabolic basis of inherited disease , مرکز فناوری اطلاعات و اطلاع رسانی کشاورزی

7,724 citations

Book
01 Jan 1989

5,306 citations

Journal ArticleDOI
TL;DR: The efficacy of different antioxidants to favorably influence the molecular mechanisms implicated in human disease should be a critical determinant of its selection for clinical studies.
Abstract: Reactive oxygen species (ROS) are implicated in the pathogenesis of a wide variety of human diseases. Recent evidence suggests that at moderately high concentrations, certain forms of ROS such as H202 may act as signal transduction messengers. To develop a better understanding of the exact mechanisms that underlie ROS-dependent disorders in biological systems, recent studies have investigated the regulation of gene expression by oxidants, antioxidants, and other determinants of the intracellular reduction-oxidation (redox) state. At least two well-defined transcription factors, nuclear factor (NF) kappa B and activator protein (AP) -1 have been identified to be regulated by the intracellular redox state. The regulation of gene expression by oxidants, antioxidants, and the redox state has emerged as a novel subdiscipline in molecular biology that has promising therapeutic implications. Binding sites of the redox-regulated transcription factors NF-kappa B and AP-1 are located in the promoter region of a large variety of genes that are directly involved in the pathogenesis of diseases, e.g., AIDS, cancer, atherosclerosis and diabetic complications. Biochemical and clinical studies have indicated that antioxidant therapy may be useful in the treatment of disease. Critical steps in the signal transduction cascade are sensitive to oxidants and antioxidants. Many basic events of cell regulation such as protein phosphorylation and binding of transcription factors to consensus sites on DNA are driven by physiological oxidant-antioxidant homeostasis, especially by the thiol-disulfide balance. Endogenous glutathione and thioredoxin systems, and the exogenous lipoate-dihydrolipoate couple may therefore be considered to be effective regulators of redox-sensitive gene expression. The efficacy of different antioxidants to favorably influence the molecular mechanisms implicated in human disease should be a critical determinant of its selection for clinical studies.

1,975 citations


"Biologic and pharmacologic regulati..." refers background in this paper

  • ...It is known that oxidant stress induces NF-kB binding activity in addition to AP-1 activity [11,12], and several studies have implicated NF-kB in the upregulation of g-GCSH expression in response to inflammatory cytokines (e....

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  • ...quences: (i) the thiol redox status of the cell will shift, activating certain oxidant response transcriptional elements [11,12], and (ii) GSSG may be preferentially secreted from the cell [13]....

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Journal ArticleDOI

1,108 citations


"Biologic and pharmacologic regulati..." refers background in this paper

  • ...Although GSH reacts spontaneously with some electrophiles [14], most such reactions require catalysis by an extended family of enzymes known as GSH S-transferases [15]....

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  • ...endogenously by the cytochrome P450 system [14–16]....

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Journal ArticleDOI
TL;DR: It is concluded that N-acetylcysteine treatment should be started within eight hours of an acetaminophen overdose, but that treatment is still indicated at least as late as 24 hours after ingestion, and it may be superior when treatment is delayed.
Abstract: During the investigational use of oral N-acetylcysteine as an antidote for poisoning with acetaminophen, 11,195 cases of suspected acetaminophen overdose were reported. We describe the outcomes of 2540 patients with acetaminophen ingestions treated with a loading dose of 140 mg of oral N-acetylcysteine per kilogram of body weight, followed four hours later by 70 mg per kilogram given every four hours for an additional 17 doses. Patients were categorized for analysis on the basis of initial plasma acetaminophen concentrations and the interval between ingestion and treatment. Hepatotoxicity developed in 6.1 percent of patients at probable risk when N-acetylcysteine was started within 10 hours of acetaminophen ingestion and in 26.4 percent of such patients when therapy was begun 10 to 24 hours after ingestion. Among patients at high risk who were treated 16 to 24 hours after an acetaminophen overdose, hepatotoxicity developed in 41 percent--a rate lower than that among historical controls. When given within eight hours of acetaminophen ingestion, N-acetylcysteine was protective regardless of the initial plasma acetaminophen concentration. There was no difference in outcome whether N-acetylcysteine was started zero to four or four to eight hours after ingestion, but efficacy decreased with further delay. There were 11 deaths among the 2540 patients (0.43 percent); in the nine fatal cases in which aminotransferase was measured before treatment, values were elevated before N-acetylcysteine was started. No deaths were clearly caused by acetaminophen among patients in whom N-acetylcysteine therapy was begun within 16 hours. We conclude that N-acetylcysteine treatment should be started within eight hours of an acetaminophen overdose, but that treatment is still indicated at least as late as 24 hours after ingestion. On the basis of available data, the 72-hour regimen of oral N-acetylcysteine is as effective as the 20-hour intravenous regimen described previously, and it may be superior when treatment is delayed.

930 citations