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Glutathione

113. Wang

XF, Cynader MS. Astrocytes provide cysteine to neurons by releasing

glutathione. J Neurochem. 2000 74(4):1434-42. PMID 10737599

“Cysteine

is the rate-limiting precursor of glutathione synthesis. Evidence suggests that

astrocytes can provide cysteine and/or glutathione to neurons. However, it is

still unclear how cysteine is released and what the mechanisms of cysteine

maintenance by astrocytes entail. In this report, we analyzed cysteine,

glutathione, and related compounds in astrocyte conditioned medium using HPLC

methods. In addition to cysteine and glutathione, cysteine-glutathione

disulfide was found in the conditioned medium. In cystine-free conditioned

medium, however, only glutathione was detected. These results suggest that

glutathione is released by astrocytes directly and that cysteine is generated

from the extracellular thiol/disulfide exchange reaction of cystine and

glutathione: glutathione + cystine<-->cysteine + cysteine-glutathione

disulfide. Conditioned medium from neuron-enriched cultures was also assayed in

the same way as astrocyte conditioned medium, and no cysteine or glutathione

was detected. This shows that neurons cannot themselves provide thiols but

instead rely on astrocytes. We analyzed cysteine and related compounds in rat

CSF and in plasma of the carotid artery and internal jugular vein. Our results

indicate that cystine is transported from blood to the CNS and that the

thiol/disulfide exchange reaction occurs in the brain in vivo. Cysteine and

glutathione are unstable and oxidized to their disulfide forms under aerobic

conditions. Therefore, constant release of glutathione by astrocytes is

essential to maintain stable levels of thiols in the CNS.”

114.

Fonnum F, Lock EA. The contributions of excitotoxicity, glutathione depletion

and DNA repair in chemically induced injury to neurones: exemplified with toxic

effects on cerebellar granule cells. J Neurochem. 2004

Feb;88(3):513-31. PMID: 14720201

“Six

chemicals, 2-halopropionic acids, thiophene, methylhalides, methylmercury,

methylazoxymethanol (MAM) and trichlorfon (Fig. 1), that cause selective

necrosis to the cerebellum, in particular to cerebellar granule cells, have

been reviewed… All six compounds decrease cerebral glutathione (GSH), due

to conjugation with the xenobiotic, thereby reducing cellular antioxidant

status and making the cells more vulnerable to reactive oxygen species.

2-Halopropionic acids and methylmercury appear to also act via an excitotoxic

mechanism leading to elevated intracellular Ca2+, increased reactive oxygen

species and ultimately impaired mitochondrial function… We propose that a

combination of reduced antioxidant status plus excitotoxicity or DNA damage is

required to cause cerebellar neuronal cell death with these chemicals. The

small size of cerebellar granule cells, the unique subunit composition of their

N-methyl-d-aspartate (NMDA) receptors, their low DNA repair ability, low levels

of calcium-binding proteins and vulnerability during postnatal brain

development and distribution of glutathione and its conjugating and

metabolizing enzymes are all important factors in determining the sensitivity

of cerebellar granule cells to toxic compounds.”

115.

Ehrhart J, Zeevalk GD. ative interaction between ascorbate and

glutathione during mitochondrial impairment in mesencephalic cultures. J

Neurochem 2003 86(6):1487-97. PMID: 12950457

“These

findings indicate that ascorbate contributes to the maintenance of GSSG/GSH

status during oxidative stress through scavenging of radical species,

attenuation of GSH efflux and redistribution of GSSG to the formation of mixed

disulfides. It is speculated that these events are linked by glutaredoxin, an

enzyme shown to contain both dehydroascorbate reductase as well as glutathione

thioltransferase activities.”

116.

Dringen R, Hirrlinger J. Glutathione pathways in the brain. Biol Chem.

2003 384(4):505-16. PMID: 12751781

“The

antioxidant glutathione (GSH) is essential for the cellular detoxification of

reactive oxygen species in brain cells. A compromised GSH system in the brain

has been connected with the oxidative stress occuring in neurological diseases.

Recent data demonstrate that besides intracellular functions GSH has also

important extracellular functions in brain. In this respect astrocytes appear

to play a key role in the GSH metabolism of the brain, since astroglial GSH

export is essential for providing GSH precursors to neurons. Of the different

brain cell types studied in vitro only astrocytes release substantial amounts

of GSH. In addition, during oxidative stress astrocytes efficiently export

glutathione disulfide (GSSG)…. This review focuses on recent

results on the export of GSH and GSSG from brain cells as well as on the

functions of extracellular GSH in the brain. In addition, implications of disturbed

GSH pathways in brain for neurodegenerative diseases will be discussed.”

117.

Pastore A et al. Analysis of glutathione: implication in redox and

detoxification. Clin Chim Acta. 2003 Jul 1;333(1):19-39. PMID:

12809732

“BACKGROUND:

Glutathione is a ubiquitous thiol-containing tripeptide, which plays a central

role in cell biology. It is implicated in the cellular defence against

xenobiotics and naturally occurring deleterious compounds, such as free

radicals and hydroperoxides… Glutathione is a critical factor in

protecting organisms against toxicity and disease. This review may turn useful

for analysing the glutathione homeostasis, whose impairment represents an

indicator of tissue oxidative status in human subjects.”

118.

Sheehan D et al. Structure, function and evolution of glutathione transferases:

implications for classification of non-mammalian members of an ancient enzyme

superfamily. Biochem J. 2001 Nov 15;360(Pt 1):1-16. PMID: 11695986

“The

glutathione transferases (GSTs; also known as glutathione S-transferases) are

major phase II detoxification enzymes found mainly in the cytosol. In addition

to their role in catalysing the conjugation of electrophilic substrates to

glutathione (GSH), these enzymes also carry out a range of other

functions.”

119.

JD, Strange RC. Glutathione S-transferase polymorphisms and their biological

consequences. Pharmacology. 2000 Sep;61(3):154-66. PMID: 10971201

“Two

supergene families encode proteins with glutathione S-transferase (GST)

activity: the family of soluble enzymes comprises at least 16 genes; the

separate family of microsomal enzymes comprises at least 6 genes. These two GST

families are believed to exert a critical role in cellular protection against

oxidative stress and toxic foreign chemicals. They detoxify a variety of

electrophilic compounds, including oxidized lipid, DNA and catechol products

generated by reactive oxygen species-induced damage to intracellular molecules.

An increasing number of GST genes are being recognized as polymorphic. Certain

alleles, particularly those that confer impaired catalytic activity (e.g.

GSTM1(*)0, GSTT1(*)0), may be associated with increased sensitivity to toxic

compounds…”

120.

Droge W, Breitkreutz R. Glutathione and immune function. Proc Nutr Soc.

2000 Nov;59(4):595-600. PMID: 11115795

“The

immune system works best if the lymphoid cells have a delicately balanced

intermediate level of glutathione. Even moderate changes in the intracellular

glutathione level have profound effects on lymphocyte functions. Certain functions,

such as the DNA synthetic response, are exquisitely sensitive to reactive

oxygen intermediates and, therefore, are favoured by high levels of the

antioxidant glutathione. Certain signal pathways, in contrast, are enhanced by

oxidative conditions and favoured by low intracellular glutathione levels. The

available evidence suggests that the lymphocytes from healthy human subjects

have, on average, an optimal glutathione level. There is no indication that

immunological functions such as resistance to infection or the response to

vaccination may be enhanced in healthy human subjects by administration of

glutathione or its precursor amino acid cysteine. However, immunological

functions in diseases that are associated with a cysteine and glutathione deficiency

may be significantly enhanced and potentially restored by cysteine

supplementation...”

121.

Functions of glutathione and glutathione disulfide in immunology and

immunopathology. FASEB J. 1994 Nov;8(14):1131-8. PMID: 7958618

“Even

a moderate increase in the cellular cysteine supply elevates the intracellular

glutathione (GSH) and glutathione disulfide (GSSG) levels and potentiates

immunological functions of lymphocytes…”

122.

Enhancement of tissue glutathione for antioxidant and immune functions in malnutrition.

Biochem Pharmacol. 1994 Jun 15;47(12):2113-23. PMID: 8031307

123.

Fernandez-Checa JC et al. Oxidative stress: role of mitochondria and

protection by glutathione. Biofactors. 1998;8(1-2):7-11. PMID:

9699001

124.

N-acetylcysteine. Altern Med Rev. 2000 Oct;5(5):467-71. PMID:

11056417 [No authors listed]

“N-acetylcysteine

(NAC) is the acetylated precursor of both the amino acid L-cysteine and reduced

glutathione (GSH). Historically it has been used as a mucolytic agent in

chronic respiratory illnesses as well as an antidote for hepatotoxicity due to

acetaminophen overdose. More recently, animal and human studies of NAC have

shown it to be a powerful antioxidant and a potential therapeutic agent in the

treatment of cancer, heart disease, HIV infection, heavy metal toxicity, and

other diseases characterized by free radical oxidant damage. NAC has also been

shown to be of some value in treating Sjogren's syndrome, smoking cessation,

influenza, hepatitis C, and myoclonus epilepsy.”

125. Cai

J et al. Inhibition of influenza infection by glutathione. Free Radic Biol

Med. 2003 Apr 1;34(7):928-36. PMID: 12654482

“Infection

by RNA virus induces oxidative stress in host cells. Accumulating evidence

suggests that cellular redox status plays an important role in regulating viral

replication and infectivity. In this study, experiments were performed to

determine whether the thiol antioxidant glutathione (GSH) blocked influenza

viral infection in cultures of Madin-Darby canine kidney cells or human small

airway epithelial cells. Protection against production of active virus

particles was observed at a low (0.05-0.1) multiplicity of infection (MOI). GSH

inhibited expression of viral matrix protein and inhibited virally induced

caspase activation and Fas upregulation. In BALB/c mice, inclusion of GSH in

the drinking water decreased viral titer in both lung and trachea homogenates 4

d after intranasal inoculation with a mouse-adapted influenza strain A/X-31.

Together, the data suggest that the thiol antioxidant GSH has an anti-influenza

activity in vitro and in vivo. Oxidative stress or other conditions that

deplete GSH in the epithelium of the oral, nasal, and upper airway may,

therefore, enhance susceptibility to influenza infection.

Tylenol depletes GSH

126.

Slattery JT et al. Dose-dependent pharmacokinetics of acetaminophen: evidence

of glutathione depletion in humans. Clin Pharmacol Ther 1987

41(4):413-8 PMID 3829578

127.

Lauterburg BH, JR. Therapeutic doses of acetaminophen stimulate

the turnover of cysteine and glutathione in man. J Hepatol. 1987

Apr;4(2):206-11. PMID 3584929

“The

data indicate that therapeutic doses of acetaminophen markedly stimulate the

rate of turnover of the pool of cysteine available for the synthesis of GSH,

most likely due to an increased rate of synthesis of GSH which is required to

detoxify the toxic metabolite of acetaminophen. Patients who are not able to

respond to a similar demand on their stores of GSH by increasing the synthesis

of GSH may be at higher risk of developing hepatic injury from drugs that

require GSH for their detoxification.”

128.

Spielberg SP. Acetaminophen toxicity in lymphocytes heterozygous for

glutathione synthetase deficiency. Can J Physiol Pharmacol 1985

63(5):468-71 PMID 4041989

Heterozygous

cells failed to use N-acetylcysteine as efficiently to resynthesize

glutathione, and the cells were not protected from acetaminophen toxicity.

Heterozygotes may be at increased risk of toxicity from drugs whose metabolites

are detoxified by glutathione conjugation.”

129.

Depletion of hepatic glutathione in rats impairs phagocytosis in vivo. Arch

Toxicol Suppl 1989;13:326-9 PMID 2774956

GSH & thimerosal

130.

Homozygous gene deletions of the glutathione S-transferases M1 and T1 are

associated with thimerosal sensitization. Int Arch Occup Environ Health 2000

73(6):384-8 PMID 11007341

131.

Muller M et al. Inhibition of the human erythrocytic

glutathione-S-transferase T1 (GST T1) by thimerosal. Int J Hyg Environ Health

2001 203(5-6):479-81. PMID 11556154

132.

Corrales F et al. Inhibition of glutathione synthesis in the liver leads to

S-adenosyl-L-methionine synthetase reduction. Hepatology 1991 14(3):528-33.

PMID 1874498

[Note

etiologic connection with thimerosal and methionine synthase, cite 20]

133.

Pajares MA et al. Modulation of rat liver S-adenosylmethionine synthetase

activity by glutathione. J Biol Chem 1992 267(25):17598-605. PMID 1517209

http://www.jbc.org/cgi/reprint/267/25/17598.pdf

[Note

etiologic connection with thimerosal and methionine synthase, cite 20]

134a.

Meister A et al. Intracellular cysteine and glutathione delivery systems. J Am

Coll Nutr. 1986;5(2):137-51. PMID 3722629

134b.

Jill & colleagues. Thimerosal Neurotoxicity is Associated with

Glutathione Depletion: Protection with Glutathione Precursors. Neurotoxicology,

in press 2004.

[Guest guest]

Since I have changed a number of things I can't say for sure that it's the glutathione cream, but I swear her immunity has improved since using it. I double the dose if she is sick- course I up her zinc and C if she is ill too. But then I had been upping those before adding the glut... so it must be the glut?? Another interesting occurance is this year is the very first time ever that her glands swelled while she was sick. Even surprised the Ped. She immediately ordered a blood test for luekemia it was such a shock. ;-) So it must have helped her immune response in a good way. Anyway- I love the cream and it's staying in our personal protocol. :-) I use Kirkman's reduced L topical. Carol in ILHoppin' Herd of Hares <feargod@...> wrote: For more on Glutathione also, here's a bit of interesting info - This abstract is suggesting that glutathione helps prevent the flu. It even mentions that oxidative stress reduces glutathione levels & therefore makes people more susceptible to flus, upper respirtory infections, etc (I hope I explained this abstract good enough!). We know that in DS they have oxidative stress going on (lots of it!) & they are also low in glutathione levels (due to the SOD process, partly). So, this abstract sure makes a whole lot of sense!! AND, provides more support for supplementing glutathione & other antioxidants. It also goes hand in hand with an article on Glutathione that I have, that talks about how people with lung issues (pulmonary fibrosis, etc) may benefit greatly from intravenous shots of Glutathione -- helps reverse the lung disease! The link for that is - http://www.thorne.com/altmedrev/fulltext/glut.html *Inhibition of influenza infection by glutathione*. Cai J, Chen Y, Seth S, Furukawa S, Compans RW, DP. Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA. jcai@... Infection by RNA virus induces oxidative stress in host cells. Accumulating evidence suggests that cellular redox status plays an important role in regulating viral replication and infectivity. In this study, experiments were performed to determine whether the thiol antioxidant glutathione (GSH) blocked influenza viral infection in cultures of Madin-Darby canine kidney cells or human small airway epithelial cells. Protection

against production of active virus particles was observed at a low (0.05-0.1) multiplicity of infection (MOI). GSH inhibited expression of viral matrix protein and inhibited virally induced caspase activation and Fas upregulation. In BALB/c mice, inclusion of GSH in the drinking water decreased viral titer in both lung and trachea homogenates 4 d after intranasal inoculation with a mouse-adapted influenza strain A/X-31. Together, the data suggest that the thiol antioxidant GSH has an anti-influenza activity in vitro and

in vivo. Oxidative stress or other conditions that deplete GSH in the epithelium of the oral, nasal, and upper airway may, therefore, enhance susceptibility to influenza infection. Qadoshyah *Got Down Syndrome? www.gotdownsyndrome.net __________________________________________________