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Ray,

I study sulfur regulation and have been concentrating on learning how the
glutamine/glutamate chemistry relates to issues of how the body handles
sulfur. A lot of the conditions you mentioned as gaining a benefit from
glutamine supplements are conditions where there is a very disturbed sulfur
chemistry.  Cytokines particularly wreak havock with the sulfur system, so
wherever chronic inflammation is a feature, sulfur problems are likely to
follow.

Several studies have found that glutamine transport across cell membranes
(and into the cell) usually stays intact during times when glutamate
transport, in contrast, has broken down.  This is would be expected because
glutamine travels into the cell via a different transport
system.  Researchers have not really figured out why glutamate transport
breaks down, although there is some interesting work on intracellular
mistrafficking of the transporter that has been found in cancer.

It is possible that you might be able to spot a problem with glutamate
transport into cells by noticing elevated glutamate levels extracellularly
in plasma or tissues.  However, the glutamate/glutamine system is
complicated enough that there certainly may be other reasons glutamate
might get elevated extracellularly. Even so, if you can get glutamine to
enter cells in lieu of glutamate, then once inside cells, glutamine can
very easily be converted into glutamate.  That glutamate can then be
incorporated into glutathione or it can participate in a very important
exchange system that is needed to keep the sulfur levels inside cells
adequate.  Glutamate inside cells can exchange for the siamese twin form of
cysteine called cystine, which is the form of cysteine that is the most
prevalent in the blood and extracellular fluid.  The point of this exchange
is to successfully bring cysteine into the cell.  This transporter is a
cystine/glutamate exchanger, so it would also be expected possibly to
deplete the cell of cystine if the extracellular glutamate is high.

Put this together and it suggests that raising extracellular glutamine
levels may end up helping transport into the cell the very cysteine that is
the rate-limiting ingredient for the formation of glutathione.  I believe
that glutathione very possibly is the most important player in the way the
body manages sulfur and that is not at all just because of its role in
redox issues.  But other than for the formation of glutathione, you also
need sulfur in the form of cysteine to furnish a lot of other sulfurish
things that the cell needs, especially the mitochondrion.

Glutathione is known to be low inside intestinal cells in many bowel
diseases.   I've put an article below that looks at celiac disease
particularly.  This particular article was not looking at treatments that
would help correct this situation other than being on the gluten-free diet.

I'm just wondering if a glutamine supplement is only likely to be helpful
in those with celiac disease whose intracellular glutathione is
depleted.  Studies looking at glutamine's help to the bowel don't seem to
be looking at this issue for the most part, so they tend not to measure the
relevant things to get data that is suitable for addressing this issue.

Of one thing I am solidly convinced: the bowel is a very special member of
the sulfur-regulating system.  Since it is so special, what happens in the
bowel may not be the same as what is happening in other tissues, or even in
the blood.

It would be interesting to hear if any listmates who had lingering bowel
problems after being on the diet for a long, long time have had doctors
that suggested doing things to replete intracellular glutathione such as IV
or transdermal glutathione, or N-acetyl cysteine, etc.

Susan  (who has started a yahoogroup recently which is called sulfurstories
for people to talk about sulfur and sulfur supplement issues:
<http://groups.yahoo.com/group/sulfurstories>http<http://groups.yahoo.com/gr
oup/sulfurstories>://groups.yahoo.com/group/<http://groups.yahoo.com/group/s
ulfurstories>sulfurstories )

  Jpn J Cancer Res 2001 Mar;92(3):279-84
    Glutathione S-transferases in small intestinal mucosa of patients with
coeliac disease.
    Wahab PJ, Peters WH, Roelofs HM, Jansen JB.
    Department of Gastroenterology and Hepatology, Rijnstate Hospital
Arnhem, PO Box 9555, 6800 TA, Arnhem, The Netherlands. [log in to unmask]

     Patients with villous atrophy due to coeliac disease have an increased
risk of developing small intestinal malignancies. Intestinal glutathione
(GSH) and glutathione S-transferases (GST) are involved in the protection
against carcinogenesis. The aim of this study was to evaluate GSH content
and GST enzyme activity in small intestinal mucosa of untreated coeliacs
compared to controls. We evaluated GSH content and GST enzyme activity,
including the levels of GST classes alpha, mu, pi and theta, in small
intestinal biopsies of untreated coeliacs (flat mucosa, Marsh IIIC, n = 12)
compared to normal subjects (n = 23). Next, we evaluated GSH and GST's in
coeliacs in remission (Marsh 0 - I, n = 11), coeliacs with persisting
villous atrophy while on a gluten-free diet (partial villous atrophy, Marsh
IIIA (n = 5); subtotal villous atrophy, Marsh IIIB (n = 6)) and patients
with infiltrative / crypt-hyperplastic Marsh II lesions (n = 4). Total GST
enzyme activity and content of GSTalpha are markedly suppressed in Marsh
IIIC lesions compared to controls (resp. 220 +/- 79 vs. 464 +/- 189 nmol /
mg protein*min (P < 0.001) and 2.79 +/- 2.46 vs. 6.47 +/- 2.29 mg / mg
protein (P < 0.001)). In coeliacs in remission these levels normalized.
Total GST enzyme activity and GSTalpha levels are proportionately lowered
according to the degree of mucosal pathology in Marsh II, IIIA and IIIB.
(Spearman's sigma correlation coefficient for total GST, -0.596, P < 0.001;
GSTalpha, -0.620, P < 0.001). GSTmu, pi and theta and GSH levels are not
significantly different in the selected study groups of mucosal pathology
compared to controls. Total GST enzyme activity and content of GSTalpha in
small intestinal mucosa are significantly lower in untreated coeliac
disease compared to controls. In Marsh II, IIIA and IIIB, GST enzyme
activity and GSTalpha content are proportionally lower according to the
degree of mucosal pathology. Normal values are seen in coeliacs in
remission. This correlation between coeliac disease and a suppressed GSH /
GST detoxification system may explain in part the carcinogenic risk in
untreated coeliac disease. PMID: 11267937

  Scand J Clin Lab Invest 1991 Apr;51(2):125-30
    Glutathione and glutathione-metabolizing enzymes in the erythrocytes of
healthy children and in children with insulin-dependent diabetes mellitus,
juvenile rheumatoid arthritis, coeliac disease and acute lymphoblastic
leukaemia.
    Stahlberg MR, Hietanen E.
>    Department of Pediatrics, University of Turku, Finland.

>    Oxidative biotransformation of xenobiotics and endogenous substances
> involves glutathione in reduced form as an integral component through two
> mechanisms: glutathione peroxidase catalysing the reduction of hydrogen
> peroxide and organic hydroperoxides, and glutathione-S-transferases
> catalysing the conjugation of oxygenated derivatives with glutathione. We
> studied glutathione and glutathione-related enzyme activities in
> haemolysed venous blood samples from 49 healthy children and from 11
> children with diabetes mellitus, 10 children with rheumatoid arthritis,
> seven children with active coeliac disease, and seven children with acute
> lymphoblastic leukaemia. Among the healthy children glutathione content
> and the activities of glutathione reductase, glutathione peroxidase, and
> glutathione-S-transferase were unrelated to sex; age-dependent
> differences were also minor. The patients with diabetes mellitus had
> decreased activity of glutathione reductase. The patients with acute
> lymphoblastic leukaemia had increased activity of both glutathione
> peroxidase and glutathione-S-transferase, possibly reflecting an adaptive
> response to free-radicals. The patients with active coeliac disease had
> control levels of all measured parameters of glutathione-related
> reactions indicating, since we earlier found decreased activities of
> glutathione peroxidase in intestinal mucosa of celiacs, that blood may
> not always reflect tissue-specific changes.PMID: 2042016

>  Amino Acids 2002;23(1-3):161-2
>    Cystine/glutamate exchange serves as the source for extracellular
> glutamate: Modifications by repeated cocaine administration.
>    Baker DA, Shen H, Kalivas PW.
>    Department of Physiology and Neuroscience, Medical University of South
> Carolina, Charleston South Carolina, U.S.A.
>
>     Repeated administration of cocaine lowers the basal extracellular
> levels of glutamate in the nucleus accumbens as measured by
> microdialysis. The studies presented reveal that this long-term
> neuroadaptation elicited by repeated cocaine results from a decrease in
> the activity of cystine/glutamate exchange.PMID: 12373531
>
>  Trends Pharmacol Sci 2002 Jul;23(7):299-302
>     Cerebral cystine uptake: a tale of two transporters.
>    McBean GJ.
>    Department of Biochemistry, Conway Institute of Biomolecular and
> Biomedical Research, University College Dublin, Belfield, Dublin 4,
> Ireland. [log in to unmask]
>
>     Transport of cystine across the cell membrane is essential for
> synthesis of the major cellular antioxidant glutathione. Cystine uptake
> in the brain occurs by both the Na(+)-independent x(c)(-)
> cystine-glutamate exchanger and the X(AG)(-) family of high-affinity,
> Na(+)-dependent glutamate transporters. New evidence concerning the role
> of cystine transport in the defence against oxidative stress is
> described.  PMID: 12119142

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