Apoptosis and glutathione

Robert Bradbury rbradbur at u.washington.edu
Sat Mar 19 20:41:29 EST 1994

In article <CMvo11.MuK at mozo.cc.purdue.edu>,
Padmakumar Narayanan <narayana at vet.vet.purdue.edu> wrote:
>I recently came across articles in NATURE and CELL that stated that a decreased
>glutathione level and an increased lipid peroxidation activity was associated
>with apoptosis in thymocytes.

>Can an increased mitochondrial respiratory activity lead to this phenomenon.
>Any thoughts about it? 
  Glutathione is one of the major cellular defenses against free radicals
and since mitochondrial respiration is one of the major pathways
producing free radicals high levels of activity lead to glutathione
depletion.  This will result in lipid peroxidation and can be measured
in animals/humans after high levels of exercise as exhaled pentane gas.

  You don't indicate how the experimentors depleted the glutathone. 
Usually this can be done by exposing cells to oxidizing agents or
xenobiotics which use up the available glutathione.  Sometimes agents
which block glutathione synthesis are used as well.  At any rate the
high concentrations of glutathione in cells it serves as a major target 
for free radicals.  If the glutathione levels are depleted the
free radicals will damage the lipids, proteins and DNA.  One of the
functions of the p53 gene seems to involve detecting high levels
of DNA damage (potentially unrepairable) and trigger an apoptosis(-like?)
response.  This makes sense from an evolutionary standpoint since
cells with high levels of DNA damage are potentially pre-cancerous
so in tissues with replacement capacity (liver, immune system, skin, etc.)
it would be better to have them commit suicide rather than risk cancer.
Unfortunately in other tissues (brain, muscle, etc.) the cells are not
replaced and you have a decline in function. 

   I was at a conference last year in which they measured levels of
glutathione in various parts of the brain.  Glutathione is synthesized
by the liver using sulfur-containing amino acids in your food (cysteine/
methionine).  The glutathione is then exported from the liver for use by
various tissues with less synthesis capacity.  In the parts of the brain
with high activity or production of damaging agents (e.g. H2O2 production
during dopamine synthesis in the S. nigra) there is a rapid decline
in glutathione levels within 3-4 hours after a meal.  This decline
probably increases the risk of cell death for cells in those brain areas.
So if one wants to live a long life with reduced risk of Parkinsons/
Alzheimers then one probably wants to eat small frequent meals which
have a fairly high sulfur content (e.g. garlic) and/or supplement with
glutathione/cysteine in an easily absorbed form (probably N-acetyl cysteine).

Robert Bradbury					bradbury at aeiveos.wa.com

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