Regulation of neuronal glutathione synthesis. [2008](IR91)

Regulation of neuronal glutathione synthesis. [2008](IR91)

Regulation of neuronal glutathione synthesis.
http://www.ncbi.nlm.nih.gov/pubmed/19008644

J Pharmacol Sci. 2008 Nov;108(3):227-38. Epub 2008 Nov 13.

Regulation of neuronal glutathione synthesis.
Aoyama K, Watabe M, Nakaki T.

Department of Pharmacology, Teikyo University School of Medicine, Itabashi, Tokyo, Japan.

Abstract
The brain is among the major organs generating large amounts of reactive oxygen species and is especially susceptible to oxidative stress. Glutathione (GSH) plays critical roles as an antioxidant, enzyme cofactor, cysteine storage form, the major redox buffer, and a neuromodulator in the central nervous system. GSH deficiency has been implicated in neurodegenerative diseases. GSH is a tripeptide comprised of glutamate, cysteine, and glycine. Cysteine is the rate-limiting substrate for GSH synthesis within neurons. Most neuronal cysteine uptake is mediated by sodium-dependent excitatory amino acid transporter (EAAT) systems, known as excitatory amino acid carrier 1 (EAAC1). Previous studies demonstrated EAAT is vulnerable to oxidative stress, leading to impaired function. A recent study found EAAC1-deficient mice to have decreased brain GSH levels and increased susceptibility to oxidative stress. The function of EAAC1 is also regulated by glutamate transporter associated protein 3-18. This review focuses on the mechanisms underlying GSH synthesis, especially those related to neuronal cysteine transport via EAAC1, as well as on the importance of GSH functions against oxidative stress.

PMID: 19008644 [PubMed - indexed for MEDLINE] Free full text

Molecular inflammation - Underpinnings of aging and age-related diseases [2009](IR91)

Molecular inflammation: Underpinnings of aging and age-related diseases [2009](IR91)

// - - Begin memo item - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - //
(Memo Item created on March 4, 2011 04:33 PM)
- - - Begin title or keyword:
Molecular inflammation: underpinnings of aging and age-related diseases.

http://www.ncbi.nlm.nih.gov/pubmed/18692159
- - - End title or keyword:

Ageing Res Rev. 2009 Jan;8(1):18-30. Epub 2008 Jul 18.

Molecular inflammation: underpinnings of aging and age-related diseases.

Chung HY, Cesari M, Anton S, Marzetti E, Giovannini S, Seo AY, Carter C, Yu BP, Leeuwenburgh C.
Department of Pharmacy, Longevity Science and Technology Institutes, Research Institute for Drug Development, Pusan National University, Geumjeong-gu, Busan 609-735, South Korea. hyjung@pusan.ac.kr

Abstract
Recent scientific studies have advanced the notion of chronic inflammation as a major risk factor underlying aging and age-related diseases. In this review, low-grade, unresolved, molecular inflammation is described as an underlying mechanism of aging and age-related diseases, which may serve as a bridge between normal aging and age-related pathological processes. Accumulated data strongly suggest that continuous (chronic) upregulation of pro-inflammatory mediators (e.g., TNF-alpha, IL-1beta, IL-6, COX-2, iNOS) are induced during the aging process due to an age-related redox imbalance that activates many pro-inflammatory signaling pathways, including the NF-kappaB signaling pathway. These pro-inflammatory molecular events are discussed in relation to their role as basic mechanisms underlying aging and age-related diseases. Further, the anti-inflammatory actions of aging-retarding caloric restriction and exercise are reviewed. Thus, the purpose of this review is to describe the molecular roles of age-related physiological functional declines and the accompanying chronic diseases associated with aging. This new view on the role of molecular inflammation as a mechanism of aging and age-related pathogenesis can provide insights into potential interventions that may affect the aging process and reduce age-related diseases, thereby promoting healthy longevity.

PMID: 18692159 [PubMed - indexed for MEDLINE]

// - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - End memo item - - //

Biologic and pharmacologic regulation of mammalian glutathione synthesis [1999](IR90)

Biologic and pharmacologic regulation of mammalian glutathione synthesis [1999](IR90)

// - - Begin memo item - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - //
(Memo Item created on January 12, 2011 07:12 PM)
- - - Begin title or keyword:
Biologic and pharmacologic regulation of mammalian glutathione synthesis

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T38-3XT71JW-3&_user=10&_coverDate=11/30/1999&_rdoc=1&_fmt=high&_orig=search&_origin=search&_sort=d&_docanchor=&view=c&_searchStrId=1604517760&_rerunOrigin=google&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=3a6b923b86116ddca74640da64f79277&searchtype=a

- - - End title or keyword:

Free Radical Biology and Medicine
Volume 27, Issues 9-10, November 1999, Pages 922-935
doi:10.1016/S0891-5849(99)00176-8 | How to Cite or Link Using DOI
Copyright © 1999 Elsevier Science Inc. All rights reserved.    

Forums

Biologic and pharmacologic regulation of mammalian glutathione synthesis

Owen W. Griffitha, 2, ,
a Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA

Available online 4 November 1999.

Abstract
Glutathione (L-γ-glutamyl-L-cysteinylglycine, GSH) is synthesized from its constituent amino acids by the sequential action of γ-glutamylcysteine synthetase (γ-GCS) and GSH synthetase. The intracellular GSH concentration, typically 1–8 mM, reflects a dynamic balance between the rate of GSH synthesis and the combined rate of GSH consumption within the cell and loss through efflux. The γ-GCS reaction is rate limiting for GSH synthesis, and regulation of γ-GCS expression and activity is critical for GSH homeostasis. Transcription of the γ-GCS subunit genes is controlled by a variety of factors through mechanisms that are not yet fully elucidated. Glutathione synthesis is also modulated by the availability of γ-GCS substrates, primarily L-cysteine, by feedback inhibition of γ-GCS by GSH, and by covalent inhibition of γ-GCS by phosphorylation or nitrosation. 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. Administration of L-cysteine precursors and other strategies allow GSH levels to be maintained under conditions that would otherwise result in GSH depletion and cytotoxicity. Conversely, inhibitors of γ-GCS have been used to deplete GSH as a strategy for increasing the sensitivity of tumors and parasites (寄生生物) to certain therapeutic interventions.

Keywords: γ-Glutamylcysteine synthetase; Free radical; Oxidative stress; Transcriptional regulation; Cysteine availability; Feedback inhibition; Nitric oxide; Buthionine sulfoximine

Abbreviations: GSH, glutathione; GSSG, glutathione disulfide; NO, nitric oxide; γ-GCS, γ-glutamylcysteine synthetase; γ-GCSH, γ-GCS heavy subunit; γ-GCSL, γ-GCS light subunit; IL-1β, interleukin-1β; TNF-α, tumor necrosis factor-α; AP-1, activator protein-1; AP-2, activator protein-2; NF-κB, nuclear factor kappa B; ARE/EpRE, antioxidant and elctrophile response elements; Sp-1, PKA, cAMP-dependent protein kinase; PKC, protein kinase C; CMK, Ca2+/calmodulin-dependent protein kinase II; OTC, 2-oxothiazolidine-4-carboxylate; BSO, buthionine sulfoximine; L-SR-BSO, L-buthionine-S,R-sulfoximine; L-S-BSO, L-buthionine-S-sulfoximine; L-S-BSO-P, L-buthionine-S-sulfoximine phosphate

Article Outline

Introduction
The enzymes of synthesis
Modulation of cellular GSH levels—Overview
Control of GSH synthesis by regulation of γ-GCS expression
Control of glutathione synthesis by substrate availability
Feedback inhibition of γ-glutamylcysteine synthetase
Regulation of γ-GCS by post-translational modification
Pharmacologic control of γ-GCS
Acknowledgements
References



Address correspondence to: Owen W. Griffith, Ph.D., Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Tel: (414) 456-8435; Fax: (414) 456-6510

2 Dr. Owen W. Griffith earned his undergraduate degree in biochemistry from the University of California, Berkeley, and completed his graduate work at the Rockefeller University in New York City working on carnitine acetyltransferase with Dr. Leonard Spector. His work on γ-glutamylcysteine synthetase (γ-GCS) began in 1975 when he joined Dr. Alton Meister's group in the Department of Biochemistry at Cornell University Medical College. Dr. Griffith joined the faculty of that Department in 1980 and continued his work on the enzymes of glutathione metabolism and on carnitine-dependent enzymes. Among his contributions are the discovery of L-buthionine-S-sulfoximine as a highly selective, physiologically active γ-GCS inhibitor and numerous studies using that inhibitor to elucidate and pharmacologically control glutathione turnover. Other current interests include nitric oxide biology and microbial defenses against oxidative and nitrosative stress. Dr. Griffith is currently Professor and Chairman of Biochemistry at the Medical College of Wisconsin, a position he accepted in 1992.

Free Radical Biology and Medicine
Volume 27, Issues 9-10, November 1999, Pages 922-935
// - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - End memo item - - //

Depletion of glutathione attenuates response of bone marrow stem cells to stromal cell-derived factor -1 [2007](IR91)

Depletion of glutathione attenuates response of bone marrow stem cells to stromal cell-derived factor -1 [2007](IR91)BK

// - - Begin memo item - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - //
(Memo Item created on December 25, 2010 11:26 PM)
- - - Begin title or keyword:
Depletion of glutathione attenuates response of bone marrow stem cells to stromal cell-derived factor -1

http://www.fasebj.org/cgi/content/meeting_abstract/21/6/A737-b
- - - End title or keyword:

FASEB J.
April 2007
21 (Meeting Abstract Supplement) A737

(The FASEB Journal. 2007;21:702.12)
© 2007 FASEB
702.12
Depletion of glutathione attenuates response of bone marrow stem cells to stromal cell-derived factor -1
Smita Swaminathan Iyer1, Jianguo Xu2, Dean P Jones2, Kenneth Brigham2 and Mauricio Rojas2
1 Nutrition and Health Sciences Program, Emory University, 615,Michael Street, 215 Whitehead Bldg, Emory University, Atlanta, GA, 30322,
2 Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, Emory University, 615,Michael Street, 205,Whitehead Bldg, Emory University, Atlanta, GA, 30322

ABSTRACT

In adult organisms, stem cells, found primarily in the bone marrow and in low numbers in other organs, are mobilized to the injured tissue where they participate in the repair process. Stromal cell-derived factor -1a (SDF-1a) is critical for stem cell trafficking during injury. Very little is known about how nutrition affects this process. Our objectives were to determine how Glutathione (GSH) depletion, observed with aging and in numerous chronic disease states, affects the functional response of bone marrow cells to SDF-1a.

Bone marrow stem cells (BMSC) from 8 week old C57BL/6J mice were isolated, and were cultured for 24 hours in buthionine sulfoximine (BSO), an inhibitor of GSH synthesis. SDF-1a (120 ng/ml) dependent chemotaxis was determined in viable cells, over 3 hours, using a modified Boyden chamber method. We found a 5 fold decline in migration, in cells depleted of GSH compared to control.

Our data show that GSH is important in the directional migration of BMSC to SDF-1a and indicate that signal transduction pathways initiated by SDF-1a may be redox sensitive. Therefore, in states of chronic oxidative imbalance, stem cell response to SDF-1a may be attenuated slowing tissue regeneration and repair. As nutrition can impact levels of GSH, dietary control of antioxidant status may provide an opportunity to enhance repair and improve recovery in patients with injury.

Classifications
Cellular Mechanisms of Nutritional Modulation in Immunity
// - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - End memo item - - //

The role of glutathione in radiation and drug induced cytotoxicity. [1987](IR91){These studies demonstrate that GSH modulation may have a major impact on the cytotoxicity of redox active drugs}.png

December 23, 2010; 06:11:10 p.m. Taipei Time

The role of glutathione in radiation and drug induced cytotoxicity. [1987](IR91).png

The role of glutathione in radiation and drug induced cytotoxicity. [1987](IR91){Diagrammatic representation of the inter-relationship of GSH with other cellular systems.}.png

The role of glutathione in radiation and drug induced cytotoxicity. [1987](IR91){These studies demonstrate that GSH modulation may have a major impact on the cytotoxicity of redox active drugs}.png

Keywords:

Clock, Watch, GSH, glutathione, interaction, mechanism, intricacy, 錯綜複雜的事物（或細節）

Glutathione Transport Is a Unique Function of the ATP-binding Cassette Protein ABCG2 [2010[(IR91)

Glutathione Transport Is a Unique Function of the ATP-binding Cassette Protein ABCG2 [2010[(IR91)

// - - Begin memo item - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - //
(Memo Item created on December 16, 2010 07:55 PM)
- - - Begin title or keyword:
Glutathione Transport Is a Unique Function of the ATP-binding Cassette Protein ABCG2

http://www.jbc.org/content/285/22/16582
- - - End title or keyword:

First Published on March 23, 2010, doi: 10.1074/jbc.M109.090506
May 28, 2010 The Journal of Biological Chemistry, 285, 16582-16587.

Glutathione Transport Is a Unique Function of the ATP-binding Cassette Protein ABCG2 *
Heather M. Brechbuhl‡, Neal Gould§, Remy Kachadourian¶, Wayne R. Riekhof¶, Dennis R. Voelker¶ and Brian J. Day§¶‖**,1
- Author Affiliations

From the Departments of ‖Medicine,
**Immunology, and
§Pharmaceutical Sciences, University of Colorado Denver Health Sciences Center, Aurora, Colorado 80045 and
the Departments of ¶Medicine and
‡Pediatrics, National Jewish Health, Denver, Colorado 80206
1 To whom correspondence should be addressed: National Jewish Health, 1400 Jackson St., Denver, CO 80206. Tel.: 303-398-1121; Fax: 303-270-2263; E-mail: dayb@njhealth.org.
Abstract

Glutathione (GSH) transport is vital for maintenance of intracellular and extracellular redox balance. Only a few human proteins have been identified as transporters of GSH, glutathione disulfide (GSSG) and/or GSH conjugates (GS-X). Human epithelial MDA1586, A549, H1975, H460, HN4, and H157 cell lines were exposed to 2′,5′-dihydroxychalcone, which induces a GSH efflux response. A real-time gene superarray for 84 proteins found in families that have a known role in GSH, GSSG, and/or GS-X transport was employed to help identify potential GSH transporters. ABCG2 was identified as the only gene in the array that closely corresponded with the magnitude of 2′,5′-dihydroxychalcone (2′,5′-DHC)-induced GSH efflux. The role of human ABCG2 as a novel GSH transporter was verified in a Saccharomyces cerevisiae galactose-inducible gene expression system. Yeast expressing human ABCG2 had 2.5-fold more extracellular GSH compared with those not expressing ABCG2. GSH efflux in ABCG2-expressing yeast was abolished by the ABCG2 substrate methotrexate (10 μM), indicating competitive inhibition. In contrast, 2′,5′-DHC treatment of ABCG2-expressing yeast increased extracellular GSH levels in a dose-dependent manner with a maximum 3.5-fold increase in GSH after 24 h. In addition, suppression of ABCG2 with short hairpin RNA or ABCG2 overexpression in human epithelial cells decreased or increased extracellular GSH levels, respectively. Our data indicate that ABCG2 is a novel GSH transporter.

ABC Transporter Antioxidant Membrane Proteins Transport Amino Acids Yeast Glutathione
Footnotes

↵* This work was supported, in whole or in part, by National Institutes of Health Grants R01 HL084469 (to B. J. D.), R01 HL075523 (to B. J. D), R01 ES0175825, R37-GM32453 (to D. R. V), and 1F32-GM076798 (to W. R. R.). This work was also supported by American Cancer Society Great-West Division Postdoctoral Fellowship Award PF-06-288-01-CSM (to W. R. R.).

↵ The on-line version of this article (available at http://www.jbc.org) contains supplemental Experimental Procedures and additional references, Figs. 1–5, and Table 1.

Received December 2, 2009.
Revision received March 23, 2010.
© 2010 by The American Society for Biochemistry and Molecular Biology, Inc.
// - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - End memo item - - //

ABCG2: structure, function and role in drug response. [2008](IR91)

ABCG2: structure, function and role in drug response. [2008](IR91)

// - - Begin memo item - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - //
(Memo Item created on December 16, 2010 10:48 PM)
- - - Begin title or keyword:
ABCG2: structure, function and role in drug response.

http://www.ncbi.nlm.nih.gov/pubmed/18370855
- - - End title or keyword:

Expert Opin Drug Metab Toxicol. 2008 Jan;4(1):1-15.
ABCG2: structure, function and role in drug response.
Polgar O, Robey RW, Bates SE.
National Cancer Institute, Medical Oncology Branch, Center for Cancer Research, NIH, 9000 Rockville Pike, Building 10, Room 13N240, Bethesda, MD 20892, USA.

Abstract
ABCG2 was discovered in multi-drug-resistant cancer cells, with the identification of chemotherapeutic agents, such as mitoxantrone, flavopiridol, methotrexate and irinotecan as substrates. Later, drugs from other therapeutic groups were also described as substrates, including antibiotics, antivirals, HMG-CoA reductase inhibitors and flavonoids. An expanding list of compounds inhibiting ABCG2 has also been generated. The wide variety of drugs transported by ABCG2 and its normal tissue distribution with highest levels in the placenta (胎盤), intestine and liver, suggest a role in protection against xenobiotics. ABCG2 also has an important role in the pharmacokinetics (藥物動力學) of its substrates. Single nucleotide polymorphisms of the gene were shown to alter either plasma concentrations of substrate drugs or levels of resistance against chemotherapeutic agents in cell lines. ABCG2 was also described as the determinant of the side population of stem cells. All these aspects of the transporter warrant further research aimed at understanding ABCG2's structure, function and regulation of expression.

PMID: 18370855 [PubMed - indexed for MEDLINE]
// - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - End memo item - - //

// - - Begin memo item - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - //
(Memo Item created on December 16, 2010 10:51 PM)
- - - Begin title or keyword:
Common added by WeiJin Tang (湯偉晉)
- - - End title or keyword:

Known GSH transporter
Glutathione Transport Is a Unique Function of the ATP-binding Cassette Protein ABCG2

ABCG2 is a GSH transporter

Source; URL of the source or Name of the professional paper:
Glutathione Transport Is a Unique Function of the ATP-binding Cassette Protein ABCG2 [2010[(IR91)
http://www.jbc.org/content/285/22/16582
// - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - End memo item - - //

// - - Begin memo item - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - //
(Memo Item created on December 16, 2010 10:56 PM)
- - - Begin title or keyword:
Auxiliary info for understanding this paper
- - - End title or keyword:

Pharmacokinetics
藥物動力學
pharmacokinetics (藥物動力學)

The branch of pharmacology concerned with the movement of drugs within the body.

The study of the action of drugs in the body: method and rate of excretion; duration of effect; etc.
Source:
wordnetweb.princeton.edu/perl/webwn

large intestine
大腸
small intestine
小腸
intestine
腸子

// - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - End memo item - - //