Dossier : Oxidative stress pathologies and antioxidants
The importance of glutathione in human disease

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Abstract

Reduced glutathione (GSH) is the most prevalent non-protein thiol in animal cells. Its de novo and salvage synthesis serves to maintain a reduced cellular environment and the tripeptide is a co-factor for many cytoplasmic enzymes and may also act as an important post-translational modification in a number of cellular proteins. The cysteine thiol acts as a nucleophile in reactions with both exogenous and endogenous electrophilic species. As a consequence, reactive oxygen species (ROS) are frequently targeted by GSH in both spontaneous and catalytic reactions. Since ROS have defined roles in cell signaling events as well as in human disease pathologies, an imbalance in expression of GSH and associated enzymes has been implicated in a variety of circumstances. Cause and effect links between GSH metabolism and diseases such as cancer, neurodegenerative diseases, cystic fibrosis (CF), HIV, and aging have been shown. Polymorphic expression of enzymes involved in GSH homeostasis influences susceptibility and progression of these conditions. This review provides an overview of the biological importance of GSH at the level of the cell and organism.

Introduction

Glutathione (GSH) is a water-soluble tripeptide composed of the amino acids glutamine, cysteine, and glycine. The thiol group is a potent reducing agent, rendering GSH the most abundant intracellular small molecule thiol, reaching millimolar concentrations in some tissues. As an important antioxidant, GSH plays a role in the detoxification of a variety of electrophilic compounds and peroxides via catalysis by glutathione S-transferases (GST) and glutathione peroxidases (GPx). The importance of GSH is evident by the widespread utility in plants, mammals, fungi and some prokaryotic organisms [1]. In addition to detoxification, GSH plays a role in other cellular reactions, including, the glyoxalase system, reduction of ribonucleotides to deoxyribonucleotides, regulation of protein and gene expression via thiol:disulfide exchange reactions [2].

The tripeptide can exist intracellularly in either an oxidized (GSSG) or reduced (GSH) state. Maintaining optimal GSH:GSSG ratios in the cell is critical to survival, hence, tight regulation of the system is imperative. A deficiency of GSH puts the cell at risk for oxidative damage. It is not surprising that an imbalance of GSH is observed in a wide range of pathologies, including, cancer, neurodegenerative disorders, cystic fibrosis (CF), HIV and aging. The role of GSH in these disorders will be discussed in this review.

Section snippets

Glutathione synthesis

GSH is synthesized de novo from the amino acids glycine, cysteine and glutamic acid. Synthesis of GSH requires the consecutive action of two enzymes, γ-glutamylcysteine synthetase (γ-GCS) and GSH synthetase [3], (Fig. 1). γ-GCS is a heterodimer composed of a catalytically active heavy subunit γ-GCS-HS (73 kDa) and a regulatory subunit, γ-GCS-LS (30 kDa) [4], [5]. The regulation of γ-GCS is complex. Induction of γ-GCS expression has been demonstrated in response to diverse stimuli in a cell

GSH redox cycle

The formation of excessive amounts of reactive O2 species (ROS), including peroxide (H2O2) and superoxide anions (O2•) is toxic to the cell. Hence, metabolizing and scavenging systems to remove them are functionally critical and tightly controlled in the cell. GSH peroxidase (GPx) in concert with catalase and superoxide dismutase (SOD) function to protect the cell from damage due to ROS. GPx detoxifies peroxides with GSH acting as an electron donor in the reduction reaction, producing GSSG as

Redox balance and glutathionylation in regulation pathways

Many drugs and chemicals can produce ROS as direct or indirect by-products. An interpretation of data from some cell survival assays suggests that low levels of ROS can have growth stimulatory effects. For example, Adriamycin undergoes redox cycling to produce quinone intermediates that provide a potent source of ROS. Using standard colony formation assays, low concentrations of Adriamycin (low nM) can actually stimulate proliferation resulting in survival above 100%. As concentrations

Polymorphism of γ-GCS

Alterations in GSH levels are associated with a wide variety of pathologies, including cancer, HIV, lung disease and Parkinson’s disease (PD). Hence polymorphisms in the genes governing GSH levels may contribute to the etiology of these disorders. Polymorphisms within the γ-GCS gene have been identified within the heavy subunit, (Table 3) [37]. The gene, located on chromosome 1, encompasses 22 kb and contains seven exons and six introns. Three alleles of the γ-GCS-HS subunit have been

Defects in enzymes of the γ-glutamyl cycle

To date, hereditary defects have been described in four of the major enzymes that mediate GSH metabolism through the γ-glutamyl cycle [66]. As mentioned previously, polymorphic variants of γ-GCS have been linked to specific diseases. However, where mutant enzyme expression occurs, the most prevalent syndromes include hemolytic anemia, either with or without hepatosplenomegaly. Hereditary defects in GSH synthetase are autosomal recessive and can lead to mental retardation and neuropsychiatric

References (102)

  • J. Alam et al.

    Identification of a second region upstream of the mouse heme oxygenase-1 gene that functions as a basal level and induce dependent transcriptional enhancer

    J Biol Chem

    (1995)
  • N.E. Ward et al.

    Irreversible inactivation of protein kinase C by glutathione

    J Biol Chem

    (1998)
  • Y. Gotoh et al.

    Reactive oxygen species and dimerization-induced activation of apoptosis signal-regulating kinase 1 in tumor necrosis factor-alpha signal transduction

    J Biol Chem

    (1998)
  • Y. Makino et al.

    Direct Association with thioredoxin allows redox regulation of glucocorticoid receptor function

    J Biol Chem

    (1999)
  • H. Shen et al.

    Identification of cysteine residues involved in disulfide formation in the inactivation of glutathione transferase P-form by hydrogen peroxide

    Arch Biochem Biophys

    (1993)
  • E.G.T. Beutler et al.

    The molecular basis of a case of y-glutamylcysteine synthetase deficiency

    Blood

    (1999)
  • L.I. McLellan et al.

    Glutathione and glutathione-dependent enzymes in cancer drug resistance

    Drug Resist Update

    (1999)
  • A.H. Tang et al.

    Biochemical characterization of Drosophila glutathione S-transferases D1 and D21

    J Biol Chem

    (1994)
  • S.G. Cho et al.

    Glutathione S-transferase mu modulates the stress-activated signals by suppressing apoptosis signal-regulating kinase 1

    J Biol Chem

    (2001)
  • R.J. Davis

    Signal transduction by the JNK group of MAP kinases

    Cell

    (2000)
  • K. Ono et al.

    The p38 signal transduction pathway: activation and function

    Cell Signal

    (2000)
  • R.C. Strange et al.

    Glutathione S-transferase: genetics and role in toxicology

    Toxicol Lett

    (2000)
  • J.L. DeJong et al.

    The human Hb (mu) class glutathione S-transferases are encoded by a dispersed gene family

    Biochem Biophys Res Commun

    (1991)
  • H.W. Lo et al.

    Structure of the human allelic glutathione S-transferase-pi gene variant, hGSTP1 C, cloned from a glioblastoma multiforme cell line

    Chem Biol Interact

    (1998)
  • E. Ristoff et al.

    Patients with genetic defects in the gamma-glutamyl cycle

    Chem Biol Interact

    (1998)
  • B. Halliwell et al.

    Oxygen free radicals and iron in relation to biology and medicine: some problems and concepts

    Arch Biochem Biophys

    (1986)
  • E.L.K. Sofic et al.

    Reduced and oxidized glutathione in the substantial nigra of patients with Parkinson’s disease

    Neurosci Lett

    (1992)
  • G.D.M. Sechi et al.

    Reduced intravenous glutathione in the treatment of early Parkinson’s disease

    Prog Neuropsychopharmacol Biol Psychiatry

    (1996)
  • R. Buhl et al.

    Systemic glutathione deficiency in symptom-free HIV-seropositive individuals

    Lancet

    (1989)
  • L. Gil et al.

    Contribution to characterization of oxidative stress in HIV/AIDS patients

    Pharmacol Res

    (2003)
  • J.C. Fernandez-Checa et al.

    S-adenosyl-L-methionine and mitochondrial reduced glutathione depletion in alcoholic liver disease

    Alcohol

    (2002)
  • V. Hudson

    Rethinking cystic fibrosis pathology: the critical role of abnormal reduced glutathione (GSH) transport caused by CFTR mutation

    Free Radical Biol M

    (2001)
  • D.H. Flint et al.

    The inactivation of Fe–S cluster containing hydro-lyases by superoxide

    J Biol Chem

    (1993)
  • P.R. Gardner et al.

    Superoxide sensitivity of the Escherichia coli aconitase

    J Biol Chem

    (1991)
  • G. Toba et al.

    Disruption of the microsomal glutathione S-transferase-like gene reduces life span of Drosophila melanogaster

    Gene

    (2000)
  • D.P. Jones et al.

    Redox analysis of human plasma allows separation of pro-oxidant events of aging from decline in antioxidant defenses

    Free Radical Biol M

    (2002)
  • P. Mullineaux et al.

    Glutathione reductase: regulation and role in oxidative stress

    Oxidative stress and the molecular biology of antioxidant defenses

    (1997)
  • M.A.A. Meister

    Glutathione

    Annu Rev Biochem

    (1983)
  • E.S.M. Sierra-Rivera et al.

    Assignment of the gene (GLCLC) that encodes the heavy subunit of y-glutamylcysteine synthetase to human chromosome 6

    Cytogenet Cell Genet

    (1995)
  • E.D.M. Sierra-Rivera et al.

    Assignment of the human gene (GLCLR) that encodes the regulatory subunit of y-glutamylcysteine synthetase to chromosome 1p21

    Cytogenet Cell Genet

    (1996)
  • S. Bannai et al.

    Amino acid transport systems

    Nature

    (1984)
  • A. Wild et al.

    Overlapping antioxidant response element and PMA response element sequences mediate basal and beta-naphthoflavone-induced expression of the human gamma-glutamylcysteine synthetase catalytic subunit gene

    Biochem J

    (1998)
  • D.L. Bella et al.

    Mechanisms involved in the regulation of key enzymes of cysteine metabolism in rat liver in vivo

    Am J Physiol

    (1999)
  • J.L. Shisler et al.

    Ultraviolet-induced cell death blocked by a selenoprotein from a human dermatotropic poxvirus

    Science

    (1998)
  • K. Okamoto et al.

    Formation of 8-hydroxy-2′-deoxyguanosine and 4-hydroxy-2-nonenal-modified proteins in human renal-cell carcinoma

    Int J Cancer

    (1994)
  • R. Chinery et al.

    Antioxidants reduce cyclooxygenase-2 expression, prostaglandin production, and proliferation in colorectal cancer cells

    Cancer Res

    (1998)
  • V.P. Roxas et al.

    Overexpression of glutathione S-transferase/glutathione peroxidase enhances the growth of transgenic tobacco seedlings during stress

    Nat Biotechnol

    (1997)
  • P. Klatt et al.

    Redox regulation of c-Jun DNA binding by reversible S-glutathiolation

    FASEB J

    (1999)
  • K. Itoh et al.

    Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain

    Genes Dev

    (1999)
  • D. Wilhelm et al.

    The level of intracellular glutathione is a key regulator for the induction of stress-activated signal transduction pathways including jun N-terminal protein kinases and p38 kinase by alkylating agents

    Mol Cell Biol

    (1997)
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