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Metabolism and Functions of Glutathione in Brain

Metabolism and Functions of Glutathione in Brain

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Metabolism and functions of glutathione in brain
Ralf Dringen
Physiologisch-chemisches Institut der Universita È t, Hoppe-Seyler-Str. 4, D-72076 Tu È bingen, Germany
Received 20 September 1999Dedicated to Professor Bernd Hamprecht on occation of his 60th birthday.
Abstract
The tripeptide glutathione is the thiol compound present in the highest concentration in cells of all organs. Glutathione hasmany physiological functions including its involvement in the defense against reactive oxygen species. The cells of the humanbrain consume about 20% of the oxygen utilized by the body but constitute only 2% of the body weight. Consequently, reactiveoxygen species which are continuously generated during oxidative metabolism will be generated in high rates within the brain.Therefore, the detoxi®cation of reactive oxygen species is an essential task within the brain and the involvement of theantioxidant glutathione in such processes is very important. The main focus of this review article will be recent results onglutathione metabolism of dierent brain cell types in culture. The glutathione content of brain cells depends strongly on theavailability of precursors for glutathione. Dierent types of brain cells prefer dierent extracellular glutathione precursors.Glutathione is involved in the disposal of peroxides by brain cells and in the protection against reactive oxygen species. Incoculture astroglial cells protect other neural cell types against the toxicity of various compounds. One mechanism for thisinteraction is the supply by astroglial cells of glutathione precursors to neighboring cells. Recent results con®rm the prominentrole of astrocytes in glutathione metabolism and the defense against reactive oxygen species in brain. These results also suggestan involvement of a compromised astroglial glutathione system in the oxidative stress reported for neurological disorders.
7
2000Elsevier Science Ltd. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6502. Functions and basic metabolism of glutathione . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6512.1. Functions of glutathione . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6512.2. Synthesis of glutathione. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6512.3. Glutathione metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6513. Glutathione in the brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6523.1. Transport of glutathione into the brain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652
Progress in Neurobiology 62 (2000) 649±6710301-0082/00/$ - see front matter
7
2000 Elsevier Science Ltd. All rights reserved.PII: S0301-0082(99)00060-Xwww.elsevier.com/locate/pneurobio
E-mail address:
ralf.dringen@uni-tuebingen.de (R. Dringen).
Abbreviations:
ADT, anethole dithiolethione; ALS, amyotrophic lateral sclerosis; ATP, adenosine triphosphate; bFGF, basic ®broblast growthfactor; BDNF, brain-derived neurotrophic factor; BSO, buthionine sulfoximine; CHP, cumene hydroperoxide; CysGly, cysteinylglycine;(CysGly)
ox
, oxidised cysteinylglycine; GDNF, glial cell line-derived neurotrophic factor; GPx, glutathione peroxidases; GR, glutathione reductase;GSH, glutathione; GST, glutathione-S-transferase(s); GSSG, glutathione disul®de;
g
GluCys,
g
-glutamylcysteine;
g
GT,
g
-glutamyl transpeptidase;LT, leukotriene; L-dopa, L-2,4-dihydroxyphenylalanine; MPP
+
, 1-methyl-4-phenylpyridinium; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri-dine; NAC, N-acetylcysteine; NADPH, nicotinamide adenine dinucleotide phosphate (reduced form); NGF, nerve growth factor; OTC, 2-oxothiazolidine-4-carboxylate; PD, Parkinson's disease; ROS, reactive oxygen species; SOD, superoxide dismutase(s); tBHP, tertiary butylhydro-peroxide.
 
3.2. Glutathione synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6533.3. Glutathione metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6533.4. Special functions of extracellular glutathione in the brain . . . . . . . . . . . . . . . . . . . . . 6544. Cell cultures as models for the investigation of neural glutathione metabolism . . . . . . . . . . . 6544.1. Astroglial cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6554.1.1. Glutathione content and synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6554.1.2. Release of glutathione . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6564.1.3. Disposal of peroxides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6564.2. Neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6574.2.1. Glutathione content and synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6574.2.2. Detoxi®cation of peroxides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6584.3. Oligodendroglial cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6584.4. Microglial cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6584.5. Interactions between dierent brain cell types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6584.5.1. Detoxi®cation of reactive oxygen species. . . . . . . . . . . . . . . . . . . . . . . . . . . 6584.5.2. Glutathione metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6594.5.3. Eect of neurotrophic factors on neuronal glutathione metabolism . . . . . . . . 6614.5.4. Harmful interactions at situations with a compromised glutathione system . . 6615. Glutathione de®ciency and neurodegeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6616. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663
1. Introduction
Oxidative stress occurs as a consequence of analteration in the equilibrium of the production of reac-tive oxygen species (ROS) and antioxidative processesin favor of the production of ROS. ROS include non-organic molecules, such as the superoxide radicalanion (O
2
À
.
), hydrogen peroxide (H
2
O
2
) and hydroxylradicals (HO
.
), as well as organic molecules such asalkoxyl and peroxyl radicals. ROS are continuouslygenerated during oxidative metabolism. In order toavoid damage caused by ROS, such as lipid peroxi-dation, protein modi®cation, and DNA strand breaks,mechanisms exist which remove ROS or prevent thegeneration of ROS (Sies, 1991; Halliwell and Gutter-idge, 1999). For example, the removal of superoxideand H
2
O
2
prevents the generation of hydroxyl radicals,which are formed by the iron-catalyzed Fenton Reac-tion or by the Haber±Weiss-Reaction (Winterbourn,1995; Wardman and Candeias, 1996) and are the mostreactive species within the ROS family.Compared to other organs the brain has some disad-vantages regarding the generation and the detoxi®ca-tion of ROS. (i) The cells of the human brain utilize20% of the oxygen consumed by the body but consti-tute only 2% of the body weight (Clarke and Sokolo,1999), indicating the potential generation of a highquantity of ROS during oxidative phosphorylation inbrain. (ii) A high content of iron has been reported forsome brain areas (Gerlach et al., 1994), which can cat-alyze the generation of ROS. (iii) The brain is rich inlipids with unsaturated fatty acids, targets for lipidperoxidation (Porter, 1984; Halliwell, 1992). (iv) Thebrain contains only low to moderate activities of superoxide dismutase (SOD), catalase, and glutathioneperoxidase (GPx) compared to liver or kidney(Cooper, 1997; Ho et al., 1997). In addition, the lossof neurons in adult brain cannot generally be compen-sated by generation of new neurons.Oxidative stress generated by ROS appears to beconnected with the loss of neurons during the pro-gression of neurodegenerative diseases, i.e., Parkinson'sdisease, Alzheimer's disease and amyotrophic lateralsclerosis (ALS) (Bains and Shaw, 1997; Cadet andBrannock, 1998; Reiter, 1998; Sun and Chen, 1998).These facts underline the importance of an eectiveantioxidant system for brain function during a longhuman life.Evidence is growing that glutathione plays an im-portant role in the detoxi®cation of ROS in brain.Glutathione de®ciency induced in newborn rats by ap-plication of an inhibitor o
g
-glutamylcysteine(
g
GluCys) synthetase, buthionine sulfoximine (BSO),leads to mitochondrial damage in brain (Jain et al.,1991). Furthermore, reduction of the brain glutathionecontent by BSO enhances the toxic eects of insultsthat are associated with elevated production of ROS,i.e., ischemia (Mizui et al., 1992) or treatment with 1-
R. Dringen/ Progress in Neurobiology 62 (2000) 649±671
650
 
methyl-4-phenylpyridinium (MPP
+
) (Wu Èllner et al.,1996) or 6-hydroxydopamine (Pileblad et al., 1989).Such results have to be considered in the context of the pathogenesis of Parkinson's disease (PD) where alowered glutathione content has been found in the
sub-stantia nigra pars compacta
(So®c et al., 1992; Sian etal., 1994a).
2. Functions and basic metabolism of glutathione
2.1. Functions of glutathione
The tripeptide glutathione (GSH;
g
-
L
-glutamyl-
L
-cysteinylglycine) is the cellular thiol present in concen-trations up to 12 mM in mammalian cells (Cooper,1997). It has important functions as antioxidant, is areaction partner for the detoxi®cation of xenobiotica,is a cofactor in isomerization reactions, and is a sto-rage and transport form of cysteine (Meister andAnderson, 1983; Cooper, 1997). In addition, gluta-thione is essential for cell proliferation (Poot et al.,1995) and maintains the thiol redox potential in cellskeeping sulfhydryl groups of proteins in the reducedform (Cotgreave and Gerdes, 1998). In addition, recentresults suggest that glutathione plays a role in theregulation of apoptosis (van den Dobbelsteen et al.,1996; Ghibelli et al., 1998; Hall, 1999).The glutathione system is very important for the cel-lular defense against ROS. A high intracellular concen-tration of glutathione protects against a variety of dierent ROS. GSH reacts directly with radicals innonenzymatic reactions (Saez et al., 1990; Winterbournand Metodiewa, 1994) and is also an electron donor inthe reduction of peroxides catalyzed by GPx (Chanceet al., 1979). It should be noted that the glutathionesystem is only part of the cellular defense systemagainst ROS. Other enzymes, such as SOD and cata-lase, as well as antioxidants, such as ascorbate and
a
-tocopherol, are also involved in ROS detoxi®cation.These compounds, their mechanism of action as wellas their interaction with the glutathione system havebeen reviewed (Di Mascio et al., 1991; Meister, 1994;Yu, 1994; Winkler et al., 1994; Jacob, 1995; Wilson,1997; Wolf et al., 1998; Gate et al., 1999).
2.2. Synthesis of glutathione
Glutathione is synthesized in vivo by the consecutiveaction of two enzymes (Meister, 1974; Fig. 1).
g
GluCyssynthetase uses glutamate and cysteine as substratesforming the dipeptide
g
GluCys which is combinedwith glycine in a reaction catalyzed by glutathionesynthetase to generate GSH. Adenosine triphosphate(ATP) is a cosubstrate for both enzymes. The intra-cellular level of glutathione is regulated by a feedbackinhibition of 
g
GluCys synthetase by the endproductGSH (Richman and Meister, 1975; Misra and Grith,1998). Therefore, cellular synthesis and consumptionof glutathione are balanced.
2.3. Glutathione metabolism
During detoxi®cation of ROS glutathione isinvolved in two types of reactions: (i) GSH reacts non-enzymatically with radicals such as the superoxide rad-
Fig. 1. Metabolism of glutathione. This ®gure describes the part of glutathione metabolism which is the focus of the present review. For adetailed review on other metabolic pathways related to glutathione see (Meister and Anderson, 1983; Cooper, 1997; Cooper and Kristal, 1997).X represents an acceptor of the
g
-glutamyl moiety transferred by
g
GT from glutathione, Y a substrate of glutathione-
-transferase(s). 1,
g
-gluta-mylcysteine synthetase; 2, glutathione synthetase; 3, glutathione peroxidase(s); 4, glutathione reductase; 5, glutathione-
-transferase(s); 6,
g
-gluta-myl transpeptidase; 7, ectopeptidase(s).
R. Dringen/ Progress in Neurobiology 62 (2000) 649±671
651

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