Re: Glutamine, Glutamate - Shakerz

[Guest guest]

Shakerz,

The first reference discusses the role mercury can play in

inhibiting a critical enzyme, glutamine synthetase, which " converts

two potentially toxic molecules, glutamate and ammonia, to the

relatively non-toxic amino acid, glutamine. "

I think that addresses one of your questions, about the enzymes

involved. And may shed some light on the discussion on mercola.com.

This conversion process is ATP dependent. One finds several

citations considering whether creatine, which can boost ATP levels,

might help increase glutamine synthetase activity. I included one

relationg to Huntington's disease.

Glutamate toxicity is a HUGE topic in recent medical research. The

notion that overconsumption of glutamine is a key player in this is

something I had never heard before, and I had trouble locating any

references that would lend credence to it.

The third and fourth citations below do address the question of

glutamine toxicity, first in rats then in pediatric oncology

patients. I included those mainly because both include ratios of

glutamine to body weight that were observed to be 'safe'. Also

because the rat study noticed changes in urine content without any

accompanying signs of morbidity, which made me think of your urine

test and wonder how relevant it really is.

I'm hoping Rich will chime in here, as our local glutamate transport

expert. You might want to review some of his posts here...sorry not

to be more helpful, I've got 'Pub Med fatigue' today and probably

wasn't doing very efficient searches.

1: Brain Res1: Brain Res. 2001 Feb 9;891(1-2):148-57.

Mercuric chloride, but not methylmercury, inhibits glutamine

synthetase activity in primary cultures of cortical astrocytes.

JW, Mutkus LA, Aschner M.

Department of Physiology and Pharmacology, Interdisciplinary Program

in Neuroscience, Wake Forest University School of Medicine, Medical

Center Boulevard, Winston-Salem, NC 27157-1083, USA.

Methylmercury (MeHg) is highly neurotoxic with an apparent dose-

related latency period between time of exposure and the appearance

of symptoms.

Astrocytes are known targets for MeHg toxicity and a site of mercury

localization within the central nervous system (CNS). Glutamine

synthetase (GS) is an enzyme localized predominately within

astrocytes. GS converts two potentially toxic molecules, glutamate

and ammonia, to the relatively non-toxic amino acid, glutamine.

During prolonged exposure to MeHg, inorganic mercury (I-Hg)

accumulates within the brain, suggesting in situ demethylation of

MeHg to I-Hg. To determine if speciation of mercurials would

differentially alter GS activity and expression, neonatal rat

primary astrocyte cultures were exposed to MeHg or mercuric chloride

(HgCl2) for 1 or 6 h. MeHg produced no changes in GS activity,

protein, or mRNA at any time or dose tested.

In contrast, HgCl2 produced a dose dependent decrease in astrocytic

GS activity at both 1 and 6 h. There were no changes in

GS protein or mRNA levels following HgCl2 exposure. Additional

studies were carried out to determine GS activity in cell lysates

incubated with HgCl2 or MeHg. In cell lysates, HgCl2 was three-times

more potent than MeHg in inhibiting GS activity. The inhibition of

GS activity in cell lysates by HgCl2 was reversed by the addition of

dithiothreitol (DTT), while DTT did not restore GS activity

following MeHg.

These data suggest that astrocytic GS activity is not inhibited by

physiologically relevant concentrations of MeHg, but is inhibited by

I-Hg, which is present in CNS following chronic MeHg exposure.

PMID: 11164818 [PubMed - indexed for MEDLINE]

*******************************************************

2: J Neurol. 2005 Jan;252(1):36-41.

Creatine supplementation lowers brain glutamate levels in

Huntington's disease.

Bender A, Auer DP, Merl T, Reilmann R, Saemann P, Yassouridis A,

Bender J, Weindl A, Dose M, Gasser T, Klopstock T.

Department of Neurology, Klinikum Grosshadern, University of Munich,

Marchioninistrasse 15, 81377 Munich, Germany.

There is evidence from in vitro and animal experiments that oral

creatine (Cr) supplementation might prevent or slow down

neurodegeneration in Huntington's disease (HD). However, this

neuroprotective effect could not be replicated in clinical trials,

possibly owing to treatment periods being too short to impact

on clinical endpoints. We used proton magnetic resonance

spectroscopy ((1)H-MRS) as a surrogate marker to evaluate the effect

of Cr supplementation on brain metabolite levels in HD. Twenty

patients (age 46+/-7.3 years, mean duration of symptoms 4.0+/-2.1

years, number of CAG repeats 44.5+/-2.7) were included. The

primary endpoint was metabolic alteration as measured by (1)H-MRS in

the parieto-occipital cortex before (t1) and after 8-10 weeks (t2)

of Cr administration. Secondary measures comprised the motor section

of the Unified Huntington's Disease Rating Scale and the Mini Mental

State Examination.

(1)H-MRS showed a 15.6% decrease of unresolved glutamate (Glu)

+glutamine (Gln; Glu+Gln=Glx; p<0.001) and a 7.8% decrease of Glu

(p<0.027) after Cr treatment. N-acetylaspartate trended to fall

(p=0.073) whereas total Cr, choline-containing compounds, glucose,

and lactate remained unchanged. There was no effect on clinical

rating scales.This cortical Glx and Glu decrease may be explained by

Cr enhancing the energy-dependent conversion of Glu to Gln via the

Glu-Gln cycle, a pathway known to be impaired in HD. Since Glu-

mediated excitotoxicity is presumably pivotal in HD pathogenesis,

these results indicate a therapeutic potential of Cr in HD. Thus,

longterm clinical trials are warranted.

Publication Types:

Clinical Trial

PMID: 15672208 [PubMed - indexed for MEDLINE]

*****************************************************

3: Int J Toxicol. 2004 Mar-Apr;23(2):107-12.

Thirteen-week oral toxicity study of L-glutamine in rats.

Tsubuku S, Hatayama K, Mawatari K, Smriga M, Kimura T.

Health Services Development Department, Ajinomoto Co. Inc., 1-15-1

Chuo-ku, 104-8315 Tokyo, Japan.

L-Glutamine (Gln) is a semiessential amino acid used in enteral

feeding in critically ill patients, and is contained in numerous

dietary supplements available to the general public. This study

evaluated toxicological effects of Gln in male and female Sprague-

Dawley rats. Gln produced by Ajinomoto Co. (Tokyo, Japan) was

incorporated into a standard diet at doses equal to 1.25%,

2.5%, and 5.0% (w/w), respectively. A control group of rats received

only a standard diet. All diets were administered ad libitum for 13

consecutive weeks.

To examine recoverability of any potential effects, the

administration period was followed by a 5-week recovery period,

during which only the standard diet was provided to all animals.

Throughout the administration and recovery periods, no deaths were

observed, and no changes in diet consumption, ophthalmologic

findings, gross pathology, and histopathology were detected. Several

changes in urine parameters (total protein, urine pH, and a positive

incidence (+/-) of ketone bodies) were observed in the 2.5% and 5.0%

groups at the end of the administration period. Minor increases were

found in hematology parameters for the 5.0% group (platelet count,

gamma-globulin, lactate dehydrogenase [LDH]), but all changes were

within physiological range. No effects of administration

were observed in the 1.25% group. The no-observed-adverse-effect

level (NOAEL) for Gln was estimated at 1.25% for both genders (males

0.83 +/- 0.01 g/kg/day; females, 0.96 +/- 0.06 g/kg/day).

PMID: 15204730 [PubMed - indexed for MEDLINE]

**********************************************************

4: Eur J Clin Nutr. 2003 Jan;57(1):31-6.

Oral glutamine in paediatric oncology patients: a dose finding study.

Ward E, Picton S, Reid U, D, Gardener C, M,

M, Holden V, Kinsey S, I, Allgar V.

Dietetic Department, St 's University Hospital, Leeds, UK.

paediatric_dietitian.sjuh@...

OBJECTIVE: The purpose of this study was to determine the most

appropriate dose of oral glutamine to use in a further clinical

study in paediatric oncology patients.

DESIGN: This was a phase I, pharmokinetic study.

SETTING: The study was carried out at The Yorkshire Regional Centre

for Paediatric Oncology and Haematology, St 's University

Hospital, Leeds, UK.

SUBJECTS: Thirteen patients undergoing treatment for paediatric

malignancy participated in this study. All 13 completed the study.

INTERVENTIONS: The most appropriate dose was determined by patient

acceptability and by plasma glutamine and ammonia levels

measured at timed intervals after ingestion of a single glutamine

dose.

RESULTS: Doses of 0.35, 0.5 and 0.65 g/kg were well tolerated with

no untoward plasma glutamine and ammonia levels. One patient was

recruited to a higher dose of 0.75 g/kg, but the plasma glutamine

and ammonia levels peaked at 2601 and 155 micro mol/l, respectively.

The ammonia level was greater than the acceptable upper limit. It

was difficult to disperse the glutamine adequately at this dose,

resulting in the suspension being found to be unpalatable and

therefore no further patients were recruited at this dose.

CONCLUSION: It was concluded that 0.65 g/kg is a safe dose of

glutamine to use in a clinical study in paediatric oncology patients.

Publication Types:

Clinical Trial

Clinical Trial, Phase I

PMID: 12548294 [PubMed - indexed for MEDLINE]

> > > This article talks about glutamine supplementation and

glutamate

> > > excitoxicity in the brain.

> > >

> > > http://www.mercola.com/2004/may/1/glutamine.htm