Glutathione Question
Greg Nigh
For those more familiar with the use and research on NAC, a question:
Given the NAC is an agent that reduces GSH so that it can function as an
antioxidant, do those who receive NAC as a therapy for immune suppression
also receive supplemental GSH?
In a related question, does the statement "low levels of GSH" in
reference to HIV+ patients only refer low levels of *reduced* GSH? What
I'm getting at is that the effectiveness of NAC seems like it might be
dependent upon the presence of non-reduced GSH, so that *if* glutathione
is not supplemented along with NAC therapy, there may not be enough GSH
around for NAC to *keep* reduced.
Any thoughts?
Greg
B4Uask
>For those more familiar with the use and research on NAC, a question:
>Given the NAC is an agent that reduces GSH so that it can function as an
>antioxidant, do those who receive NAC as a therapy for immune suppression
>also receive supplemental GSH?
I had this close at hand but have recently read that oral Glutathione
supplementation is not bioavailable because of gut enzymes and that NAC is
necessary for the bodies own creation of the compound, the components of
which are contained in NAC.
Title: GSH rescue by N-acetylcysteine.
Date of Pub: 1991 Nov 15 Author: Ruffmann R; Wendel A;
Issue/Part/Supplement: 18 Volume Issue: 69 Pagination: 857-62 MESH
Abstract: Reduced glutathione (GSH) is the main intracellular low
molecular weight thiol. GSH acts as a nucleophilic scavenger and as an
enzyme-catalyzed antioxidant in the event of electrophilic/oxidative
tissue injury. Therefore, GSH has a major role as a protector of
biological structures and functions. GSH depletion has been recognized as
a hazardous condition during paracetamol intoxication. Conversely, GSH
rescue, meaning recovery of the protective potential of GSH by early
administration of N-acetylcysteine (NAC), has been found to be
life-saving. Lack of GSH and electrophilic/oxidative injury have been
identified among the causes of the adult respiratory distress syndrome
(ARDS), idiopathic pulmonary fibrosis (IPF), and the acquired
immunodeficiency syndrome (AIDS). Experimental and early clinical data (in
ARDS) point to the role of NAC in the treatment of these conditions.
Recently, orally given NAC has been shown to enhance the levels of GSH in
the liver, in plasma, and notably in the bronchoalveolar lavage fluid.
Rescue of GSH through NAC needs to be appreciated as an independent
treatment modality for an array of different disease, all of which have
one feature in common: pathogenetically relevant loss of GSH. Record Type:
MJ Abstract By: Author Address: Inpharzam SA, Cadempino, Schweiz. Number
of References: 34
Cameron Snyder
**********
"Aids" promoters...should all be lined up against a wall and shot.
You can't get "Aids" from sex, of any kind... We have plenty of sex,
and our "Aids" is drying up...
John@himself
George M. Carter
Greg Nigh <gn...@enuxsa.eas.asu.edu> wrote:
>For those more familiar with the use and research on NAC, a question:
>In a related question, does the statement "low levels of GSH" in
>reference to HIV+ patients only refer low levels of *reduced* GSH? What
>I'm getting at is that the effectiveness of NAC seems like it might be
>dependent upon the presence of non-reduced GSH, so that *if* glutathione
>is not supplemented along with NAC therapy, there may not be enough GSH
>around for NAC to *keep* reduced.
>Any thoughts?
It depends on whether glutathione (GSH) is lost through the
mercapturate pathway or if it is oxidized to GSSH. The attached is
part of a draft article.
George M. Carter
Glutathione
(And Ways to Increase Levels)
Note: This Information Sheet contains an extra section entitled: What
Other Ways Might Help Increase Glutathione Levels Inside Cells? (found
after the section, What Are the Best Forms?). Most research shows that
consuming glutathione directly does not help to replenish losses
inside cells. However, there is some evidence that it can be broken
down, transported into cells and then reformed as whole glutathione.
Further, there may be some value to having extracellular glutathione
available along the GI tract where roughly 60% of your immune cells
and organs reside. In any event, this section outlines some of the
proposed means other than direct consumption of glutathione that may
help cells to produce their own glutathione.
What Is It?
Glutathione is a small piece of a protein, known as a peptide.
Peptides are small portions of proteins. Proteins are made up of
strings of amino acids that fold into a specific shape. When you eat
proteins, they are broken down by enzymes in the intestines into
peptides and then, eventually, into the building-block amino acids.
(Enzymes are proteins that help to make a particular reaction go far
more rapidly than if the reactants were just left to themselves.)
Amino acids then move to the liver where they are stored, sent out
into the plasma, broken down into sugars (glycogenic amino acids) or
fats (ketogenic amino acids), or utilized to build other proteins.
Three amino acids make up glutathione: cysteine, glutamic acid
(glutamate) and glycine. Another name for glutathione is
"gammaglutamylcyteinylglycine". Cysteine is an "essential" amino acid,
meaning that the body must take it in from dietary sources and can not
manufacture it on its own. These three amino acids makes glutathione a
tripeptide. (A peptide with 2 amino acids is a dipeptide). (See also
the Information Sheet on NAC which is an acetylated cysteine).
Glutathione is commonly abbreviated to "GSH." The "SH" refers to the
important sulfur-hydrogen molecule found in the cysteine and which is
known as a thiol. Cysteine is the "active" part of the glutathione
tripeptide, since it is this -SH group which donates electrons to
quench free radicals (see the Oxidative Stress section of TIP). Amino
acids which contain the element sulfur are known as "sulfur-containing
amino acids." Cysteine, methionine and taurine are the
sulfur-containing amino acids. The simplest way GSH is built
(synthesized), the glutamate is connected to the cysteine (becoming
gamma-glutamylcysteine) which then (inside the cell) has the glycine
attached. Voila: new glutathione! (Schroder, 1996).
Free radicals are molecules that are missing an electron. Usually
electrons come in pairs. This creates problems when free radicals bump
into the cell’s membrane, other proteins or even DNA: their greedy
acquisition of electrons results in those tissues being damaged
through chain reactions. GSH prevents this by donating an electron.
The sulfur atom in the cysteine makes a bridge with a sulfur atom in
the other GSH peptide, donating an electron to the errant free
radical, calming it down. Or GSH may directly bind to a free radical,
creating a mixed disulfide. The chemistry of reduction (acquiring an
electron) and oxidation (donating an electron) is a fundamental aspect
of the way our bodies function. When this chemistry is significantly
and chronically awry, disease may ensue or be worsened.
The thiol form is the active form. The GSH form is the reduced form
(can provide an electron), while the "double-GSH" (disulfide) GSSG
form is the oxidized form (has donated the electron). When GSH meets
another protein or thiol and connects to create a disulfide bridge, it
no longer quenches free radicals (it is oxidized: GSSG) and must be
reduced back to the thiol form (GSH) to continue its work. This
process, of going from an active reduced state to oxidized, also
happens when two cysteines alone (thiol amino acids) hook up to become
the disulfide, cystine, the oxidized form of cysteine (see the
Information Sheet on NAC). That is, cystine is two cysteines linked
together. The balance inside cells between the amount of thiols and
disulfides has important consequences to the rate of cell division and
immune response (Broome, 1973; Deneke, 1989).
The balance of the amount of thiols (GSH) to oxidized (GSSG) is
tightly regulated. It is difficult to alter the overall ratio inside a
cell. Various mechanisms come into play to maintain the ideal balance.
However, when stresses like free radicals come into play, they may
damage that tightly-controlled regulation with devastating
consequences (Taylor, 1996).
Where do free radicals come from? Many sources, including smoking,
oxygen and some other drug therapies, protein-energy malnutrition,
pollution and the ultraviolet (UV) part of sunlight. (Remember, the
solar spectrum we see goes from blue to red; UV is part of the blue
beyond what our eyes can see, but its effects are readily apparent in
lighter skinned people who stay in the sun too long!)
Also, free radicals arise from the body’s response to an infection,
which generates a lot of free radicals used to destroy the invader.
The "fire" thus produced can be put out (quenched) by chemicals inside
cells, the most important quenchers being superoxide dismutases,
catalase and glutathione. An infection will also light such a free
radical fire (Taylor, 1996). Normally, the body’s hellish, free
radical attack upon an infection clears it from the body, but, if the
enemy eludes this response, there is chronic warfare and subsequent
damage. Unfortunately, because HIV is a chronic condition, the body is
in a continual state of response to the infection, and thus is
constantly generating damaging free radicals. This may be one reason
the intracellular (inside cells) stores of glutathione are used up.
Studies have documented dramatically reduced or deficient levels of
glutathione stores in many people with HIV (Buhl, 1989; Droge, 1988;
Staal, 1992).
Glutathione is found in all cells and organs, highest levels being
found in the liver, spleen, kidneys (which are, among other things,
detoxification organs) and the pancreas. Also, the eye (lens and
cornea) has large amounts of glutathione. The lungs, heart and central
nervous system (CNS) also contain significant amounts of glutathione.
As is discussed below, glutathione has multiple functions, including
as an antioxidant, heavy metal detoxifier, protecting red blood cell
integrity and as a transporter of various proteins. It also helps to
regenerate vitamin C (Lomaestro, 1995; Braverman, 1987). In the
Lomaestro review, they note that "[Glutathione] is considered to be
the most prevalent and most important intracellular nonprotein
thiol/sulfhydryl compound in mammalian cells, and the most abundant
low-molecular weight peptide." Please note under "Is It Toxic?" the
warnings regarding people with active cancer (lymphoma being
particularly relevant to some PWHIV).
Are There Deficiencies In HIV Infection?
Yes. The blood (plasma) and lung fluids (lung epithelial lining fluid)
of PWHIV were checked for total and reduced glutathione levels as
early as 1989. Buhl and his colleagues looked at 14 asymptomatic
people. Plasma levels of GSH were found to be 30% that of uninfected
people. This is a plasma reduction of 70%! The mean numbers were 5.99
micromolar/liter of glutathione in HIV-negative subjects and 1.97 in
HIV+ folks. Further, the lung fluids had about 60% as much as controls
(Buhl, 1989).
However, this does not tell us how much GSH is actually inside immune
cells, which is also very important. One group showed that the
glutathione level becomes depleted in CD4+ cells as well as CD8+
cells. They noted that GSH was 63% of normal in AIDS and 66% of normal
on ARC in CD4+ cells, or a loss glutathione of 37% and 34%,
respectively in people with AIDS or ARC. Similarly, in CD8+ cells GSH
was 62% of normal in AIDS and 69% of normal in ARC (Staal, 1992).
Others have pointed out that a loss of 20-30% of intracellular
glutathione "has the consequence of impairing this defense, allowing
cell injury to proceed until cell death occurs" (Ruffmann, 1991).
"This defense" refers to the observation that "…GSH is considered to
be an outstanding protector of biological structures and function."
Thus, the evidence points strongly to a serious depletion of
glutathione which has devastating consequences to cell function and
survival.
Dr. Wulf Droge, one of the researchers who discovered the GSH
deficiency in 1989, states that AIDS is to some degree the result of
an HIV-induced cysteine deficiency. Cysteine is vital in the synthesis
of glutathione: if there isn’t enough cysteine available, glutathione
levels fall. Droge examined the GSH levels in several primate (monkey)
models who do not proceed to immune suppression after being infected
with SIV or HIV. He reported that these animals (African green monkeys
and chimpanzees, specifically), unlike humans, never lose the
substantial amounts of GSH and other thiols within their blood or
inside their immune cells. AIDS does not develop. In contrast, both
humans and SIV-infected rhesus macaques do see loss of glutathione and
cysteine and develop AIDS (Droge, 1994; Droge, Pharmacology, 1993).
These experiments showed further that this reduction in extracellular
(outside the cell) cysteine was associated with the loss of
intracellular (inside the cell) glutathione. If cysteine is not
available, new glutathione peptides are not formed. Since glutamic
acid and glycine are found in plentiful supply inside cells, it is the
cysteine portion of the tripeptide which must be actively brought
inside the cells. Therefore, cysteine is the rate-limiting step (how
fast it can go) in the synthesis of glutathione. One more reason why
NAC, an acetylated form of cysteine, seems to be important in people
with HIV (Ruffmann, 1991).
Some researchers have noted that it is this initial loss of GSH when a
person is first infected which causes the critical, viral-controlling
CTLs (cytotoxic T-lymphocytes) to disappear soon after initial
infection (Fauci, 1996). In his testimony in 1995 to the review panel
of the Office of AIDS Research (known as the NIH AIDS Research Program
Evaluation Working Group), Fred Bingham (DAAIR’s Executive Director
and a PWA) noted the early loss of cytotoxic T cells (CTLs) which
require very high concentrations of glutathione. Without these immune
cells the body can not adequately control HIV infection and so the
beginning of the fatal progression of the immune dysregulation
syndrome. Bingham further suggests the possibility that cytotoxic
cells exist that are more strongly active than others. Like the layers
of an onion, the strongest CTLs are the most sensitive to losses in
glutathione. These cells are lost earliest in the first onslaught
against the invasion by HIV.
The Stanford group (see references for Roederer and Herzenbergs) has
indeed found evidence showing generally higher concentrations of
glutathione in monocytes and macrophages, say, than B cells: "B cells
have the lowest GSH levels; T cells are intermediate; and monocytes
and macrophages have the highest levels" (Roederer, 1991). In the same
article’s abstract, they go on to state: "Furthermore, GSH levels
subdivide the CD4 and CD8 T cell subsets into two classes each: high-
and low-GSH cells, which cannot be distinguished by cell size or by
currently known surface markers. Significantly, the high-GSH T cells
are selectively depleted early during the HIV infection, and are
effectively missing in all ARC and AIDS patients."
Droge and his group have suggested that keeping the glutathione levels
within the normal range may help to keep the virus at bay. But once
this delicate balance is damaged by too great a loss of glutathione,
the scales tip in favor of enhanced HIV replication—and AIDS develops.
Aside from the numerous critical immune-related functions requiring
adequate levels of glutathione, the loss of glutathione inside of
cells leads to excesses in free radicals. This, in turn leads to
heightened activation of free-radical sensitive switches on HIV which
either turn on latent (asleep) virus, or dramatically increase active
HIV replication. Higher free radical levels within cells also leads to
heightened activation of the immune cells—which means heightened HIV
activity as well.
Certainly, somewhat similar immunological defects occur in chronic
fatigue syndrome and Lou Gehrig’s disease (amyotrophic lateral
sclerosis) that bear a similarity to AIDS (lowering of CD4/CD8 ratio,
loss of natural killer cell function). Here too, a loss of glutathione
is seen. However, the immunological dysregulation is nowhere near as
severe as with AIDS and clearly the catastrophic immunological
destruction seen in AIDS is a result of the many problems that arise
as a direct result of HIV infection (and possibly co-infections like
HHV-6). But the crucial pivot in this aspect of AIDS is glutathione
(Droge, 1996).
However, not everyone with HIV has reduced glutathione levels. What
does this mean? Some researchers have noted that people who started
out with low levels progressed much more quickly than those with
normal levels at the start of their study (Herzenberg, 1996). This
underscores the importance of glutathione as part of the whole system
in dampening oxidative stress. Higher glutathione levels may be part
of the reason that some people remain long-term survivors since their
bodies are able to effectively manage the HIV without over-reacting
and causing more tissue damage and viral activation.
If glutathione is low and tissue damage is increasing, this creates
the very type of environment in which HIV thrives. Low glutathione
levels may also allow further killing of uninfected "bystander" T
cells by apoptosis (Badley, 1996) possibly through the increased
oxidative stress generated by fighting HIV and which has been shown to
increase apoptosis (Slater, 1995). If this is the case, then helping
the body to maintain normal levels in people whose stores are low may
help to improve their survival.advocating strongly that the NIH
conduct multifactorial regimen studies. Your help is vital (and yes,
politics DO have an impact on our health).
In other studies by Droge’s group, an association was made between the
lower levels of glutathione and cysteine and an increased amount of
another amino acid, glutamate in the plasma. Glutamate levels were up
to six times higher than in non-HIV infected subjects. This was noted
not only in peripheral blood cells (PBMC), but particularly in
monocytes from HIV-infected people (Eck, 1989). Glutamate elevations
in plasma of PWHIV were associated with reduced amounts of cysteine
(and cystine) inside cells. This may explain while supplementing with
NAC and other glutathione inducers are only partially successful.
(It’s important to remember that the levels in the plasma versus in
tissues or inside immune cells all have different meanings.
Intracellular glutamate is important to keep high, but when too much
is out in the plasma, it suggests that the mechanism for transporting
glutamate to tissues is not working properly). It’s a complicated
story but the following is the "Cliff Notes" version:
Droge’s group noted that macrophages first take in the oxidized form
of cysteine, cystine (2 connected cysteines). They later release
electron rich (reduced) cysteine into the immediate plasma surrounding
T-cells when docking with those cells in order to give them their
instructions. Therefore the macrophage acts as a "cysteine-pump,"
feeding highly reactive (easily donating an electron and therefore
unstable) reduced cyteine in extremely close proximity to the T-cell,
in order for the cysteine to be easily moved into the cell and used
before it has a chance to become oxidized (unusable, oxidized
[electron-poor] cystine as opposed to usable, reduced [electron rich]
cysteine). This T-cell uptake of electron-rich cysteine is blocked by
the excessive amounts of glutamate found in the plasma (Droge, 1991).
Adding either cystine or methionine (a precursor to cysteine) had no
effect on improving the intracellular concentration of cysteine in T
cells or release of cysteine by macrophages in laboratory conditions.
High levels of glutamate also can block glutathione synthesis in other
cells as well. As was mentioned at the beginning of this sheet,
glutathione is manufactured from three amino acids, glutamate,
cysteine and glycine, and it’s proper name is gamma-glutamyl
(glutamate)-cysteinyl (reduced cysteine)-glycine. Unfortunately the
gamma-glutamyl portion of the tripeptide is not specific for just
cysteine (cysteinyl) but also accepts glutamate as well (Deneke,
1989). With six times the normal levels of glutamate in plasma, when
the body goes to manufacture the first portion of glutathione
(gammaglutamylcysteinyl) it ends up making useless
gammaglutamylglutamate instead.
Excess plasma glutamate has been shown to block the uptake of cystine
by endothelial cells as well (Miura, 1992). Others have found that the
excess glutamate blocks cystine uptake into macrophages and peripheral
blood mononuclear cells (Eck and Droge, 1989; Gmunder, 1991). This
particularly occurs in people with wasting; the muscle tissue doesn’t
take up the glutamate and convert it into glutamine which is the major
amino acid used for creating muscle tissue. Why this system fails is
not understood.
The limited ability of simply adding cysteine or methionine to improve
GSH levels may partly explain why GSH-replenishment drugs like NAC and
OTC have some usefulness, but less than what many researchers had
hoped. As mentioned, glutamate levels are up to six times the normal
levels in persons infected with HIV (Eck, 1989), which suggests that
at least six times the normal levels of cysteine are needed in the
extracellular fluid immediately surrounding T cells to offset the
blocking effects of the glutamate on intracellular GSH levels. (Here,
we refer to the supposition that glutamate competitively binds with
the gamma-glutamyl moiety and does not bind to the cysteine, see
paragraph above.) T cells are extremely dependent on GSH levels for
their ability to function and to not be destroyed by apoptosis
(premature cell suicide activated by excess free radicals inside the
cell). This is why, under free-radical generating chemotherapy and
radiation and the ongoing battle against HIV, the very first things to
disappear (by apoptosis) in your body are various subsets of T-cells
(Roederer, 1991). High levels of glutamate may partially explain the
abnormally high levels of apoptosis seen during the course of HIV
infection. There is at the very least evidence that periodic
elevations of glutamate seen in AIDS may induce an apoptotic like
mechanism in neurons (Dreyer, 1995; Carter, 1993).
In trying to understand the reason for this elevated glutamate, Droge
and his colleagues looked also at healthy individuals who underwent
"anaerobic" exercise, with or without use of NAC. They noted that even
some healthy people were at risk for loss of body cell mass under
heavy exercise conditions, and this was correlated to a higher level
of glutamate in the venous blood. This is partly due to the excessive
exercise overwhelming the body’s ability to make sufficient ATP to
offset the high rate of glycolytic activity (breakdown of sugars).
When this happens, the muscles excrete a fair amount of chemicals
called pyruvate and lactate. As they do this, they also take some
protons, often derived from local stores of cysteine which otherwise
would be used to synthesize glutathione. (Remember, a proton is a
hydrogen atom missing an electron). Meanwhile, glutamate builds up in
the blood and is blocked from entering into the muscle tissues. Voila:
muscle tissues deteriorate (Kinscherf, 1996).
In the meantime, it has been shown that people with HIV need to
consume a great deal more calories to provide the body the needed
energy to repair damaged tissue and to fight the virus (Hogg, 1995).
Obviously, if the building blocks and tools needed to regenerate
glutathione and offset the oxidative stress are missing, a vicious
cycle is perpetuated that reduces immunity and permits opportunistic
infections to get a foothold which drives an increase in TNF (Taylor,
1996). Thus, opportunistic infections (parasites being particularly
problematic) play a significant role in that the increase in TNF the
body uses to respond to them tends to increase oxidative stress, HIV
replication and further the negative downward spiral. It can only be
hoped that nutritional repletion will help to rebalance the abnormal
amino acid profile and prevent OIs from getting a foothold—and we have
some anecdotal evidence that this may occur. But, again, an important
question is eclipsed by ignorance and greed. (Of course, let us be
clear that this underscores the need for aggressive diagnosis and
treatment of OIs.)
Droge’s group hypothesizes that there are two stages to wasting
(cachexia) as is seen in cancer and AIDS that may explain the varied
levels of amino acids seen at different points in HIV disease. Wasting
causes a particular destruction of the lean tissue or skeletal muscle.
The first stage is a "pre-cachectic" condition described as a "pull,"
in which the liver’s need for more glutathione to deal with the
oxidative stress draws more glutamate and other amino acids from
tissues (or conversely, inhibits the transport of glutamate from the
plasma into the skeletal muscle tissues where they are needed to make
glutamine, thus further draining the levels of ATP as more glutamine
is synthesized: glutamine levels have also been found to be low in
PWHIV; Droge, 1996). The ability of the mitochondria to produce the
amount of ATP needed is overwhelmed by conditions of chronic stress
produced by HIV infection (or AZT use). In this "pull" stage, there is
no overt manifestation of loss in body cell mass, but various
biological markers are triggered, notably reductions in plasma amino
acid levels. As this process progresses, there is a "push" phase,
where the body’s skeletal muscle pushes out more amino acids for
utilization as energy sources. This model effectively clarifies the
observations of greater amounts of plasma levels of some amino acids
seen in later stages (Kinscherf, 1996; Droge, 1996).
Researchers from the University of Toronto reported on glutathione and
cysteine deficiencies, noting that they were reduced 30-35% relative
to controls in plasma and peripheral blood lymphocytes. They also
noted an increase in the disulfide form, GSSG, suggesting that the
glutathione reductions seen in this compartment are associated with
oxidation of GSH (as opposed to conjugation and loss through the
mercapturate pathway—see below). They underscore the potential of NAC
in therapy (Walmsley, 1996). Others reported increases in glutathione
peroxidase (indicating GSH loss through oxidation) and other
characteristics of increased oxidative stress such as increased levels
of malondialdehyde (Trotti, 1996).
Please review the Information Sheet on NAC (N-acetyl-cysteine) for
related information.
What Does Glutathione (GSH) Do? How Does It Work In HIV Infection?
This particular little peptide performs a great variety of roles. It’s
first identified role was shuttling other proteins within the cell.
Its more central role as a broadly-acting antioxidant has been more
deeply understood over the last 10 years or so (Hamilos, 1992). GSH
also acts as a detoxifier, helping to remove dangerous heavy metals
and pharmaceutical drug metabolites from the body as well as in DNA
synthesis and repair, protein and prostaglandin synthesis, amino acid
transport, metabolism of toxins and carcinogens, enhancement of immune
system function, prevention of oxidative cell damage and enzyme
activation (Lomaestro, 1995).
Metabolic Activities
The enzyme systems in which GSH is involved have an impact on a wide
range of other important enzyme systems involving the breakdown and
utilization of sugars, starches and proteins as well as immune
function and other bodily activities (Ziegler, 1985). Additionally,
GSH participates in the metabolism of other cellular products like
prostaglandins, estrogen and leukotrienes (Meister, 1983) as well as
in the transformation of deoxyribonucleotide to the
deoxyribonucleotide building blocks of DNA (Meister, 1991).
Understanding how GSH is lost and what can be done to restore the
system may go a way toward offsetting the multifactorial damage
induced by HIV.
GSH is involved in complicated cycles that involves many other
important enzymes. The enzymes involved in the glutathione cycle
perform a wide variety of functions, transforming (or, one might say,
"morphing") the glutathione from a reduced form to an oxidized form or
transforming it into other molecules. A variety of diseases have at
their root a defect somewhere in this dance of enzymes. Just one
enzyme malfunctioning or absent can result in severe glutathione
deficiency. For example, people with an inborn deficiency in the
enzyme that converts the GSSG back to GSH (GSSG reductase) suffer from
hemolysis (red blood cell destruction) and early development of
cataracts (Meister, 1991).
There are two broad cycles or transformational paths that GSH may
follow. One is simple: glutathione is oxidized (donates an electron)
to the disulfide, GSSG. (Or it may bind to another protein, GSX,
making a mixed disulfide). This oxidation is part of the process of
mopping up damaging free radicals and is carried out by glutathione
peroxidases (GPx), many of which require selenium. When GSH is
oxidized to GSSG, it can be converted back to glutathione by reductase
enzymes and some energy (from the NADPH molecule). However, if the
oxidative stress is constant, the reductase enzyme is overwhelmed and
the cell can be filled with too much GSSG. Since this can be damaging,
the excess GSSG is shuttled out of the cell, causing an irreversible
loss of GSH (Lomaestro, 1995; Meister, 1991; Deneke, 1989).
The other pathway is a more complicated system known as the
mercapturate pathway. There are many enzymes involved in these
pathways, including, glutathione synthetase, gamma-glutamyl
transpeptidase and other transpeptidases, 5-oxoprolinase and a variety
of others. Ruffmann notes, "Conjugated GSH, however, is exported from
the cell and processed to mercapturic acids, which are excreted in the
urine. In these reactions, GSH is lost irreversibly and can be
replaced only via ex novo synthesis." (Ex novo means that GSH has to
be created in the cell from building blocks found inside or brought in
from outside the cell). The cysteine moiety binds to a toxin, often an
aromatic compound (that has rings, like benzene and many
pharmaceutical drugs). This conjugated couple is taken out of the cell
and eventually excreted in the urine as mercapturic acids. Thus, to
replenish the supply of glutathione in the cell, more needs to be made
(synthesized). For the cell to resynthesize glutathione after it has
been exported out of the cell requires energy from the energy-storing
molecule ATP (in the mercapturate pathway) (Meister, 1983; Ruffmann,
1991). Please see the further discussion under the Detoxification
segment below.
These cycles are, to put it mildly, an extremely complicated system
and exactly how it is dysregulated in people with HIV is not
understood yet. Is glutathione lost by oxidation to GSSG or by the
mercapturate pathway? If both—is more GSH lost through one pathway
than the other? Are many uninfected cells being depleted of
glutathione? Despite the importance of these questions and their
relevance to the health of people with HIV, few clinical data are
available. This is truly an indictment of a system subservient to the
greed of the pharmaceutical industry. Profit over life.
While oral consumption of GSH may get into the cells along the GI
tract, the cells in the blood plasma doesn’t necessarily take up this
ingested glutathione. Health Maintenance is currently conducting a
study on the bioavailability of glutathione and the effect on people
with HIV. The study is using 3 grams per day. Unfortunately, results
will probably not be available before 1997 (personal communication).
Another study of 3 grams of oral use showed no elevation in plasma
glutathione (Witschi, 1992).
Antioxidant Functions
Electron-rich glutathione acts either directly or indirectly as an
antioxidant. Directly, it can be converted to the disulfide GSSG form
(or a mixed disulfide of GSH and another protein), donating electrons
and reducing free radicals like superoxides and hydrogen peroxide.
Indirectly, it can work with the important enzymes, glutathione
peroxidase and phospholipid hydroperoxide GSH peroxidase (Lomaestro,
1995).
Importantly, GSH helps other vitamins in the body. When a free radical
is given an electron (or bound), the payer (vitamin C) is now in an
oxidized form and needs an electron. The glutathione enzyme system
reduces the oxidized form of vitamin C. In turn this reinvigorated
vitamin C can reduce oxidized vitamin E back to its stabilized form
(Tappel, 1968). Unfortunately, GSH is converted to GSSG and needs to
be reduced itself, reinforcing the need for a balanced approach to
antioxidant use that includes a good blend of vitamins as well as
sufficient supply of sulfur-containing amino acids.
Re-supplying GSH in HIV/AIDS is thus essential for restoring vital
vitamin C and E antioxidant action, protecting cells/organs against
oxidative damage of various types. This helps to restore immune
responsiveness which can slow or stop chronic intracellular viral
activation (Droge in Pharmacology 1993; Barbarini, 1994; Buhl, 1989),
as well as performing many other critical immune functions. When there
is a global sulfur (thiol) deficiency, it helps stimulate HIV
replication which accelerates disease progression.
In addition, the HIV protein known as tat strongly inhibits the enzyme
manganese SOD. MnSOD is responsible for regenerating GSH inside the
mitochondria, the cells’ energy producing factory (Carter, 1993). It
is very likely that this mechanism adds substantially to immune cell
loss through apoptosis.
Immune Modulation and Anti-inflammatory Functions
(Don’t forget to review the Immunology Primer in TIP.)
Adequate levels of GSH are required for various aspects of the immune
response, including mixed lymphocyte reactions, T-cell proliferation,
T and B cell differentiation, cytotoxic T-cell activity and natural
killer cell activity (Meister, 1988; Hamilos, 1992 and 1985; Droge,
1986; Suthanthiran, 1990; Anderson, 1993). Compounds that replenish
GSH help to counteract oxidative stress. This creates an environment
that is not conducive to HIV replication. However, to the extent GSH
repletion helps to induce T-cell activation, this can be a
double-edged sword. On the one hand, it may help restore cell mediated
immunity and protect uninfected T-cell killing; on the other, it may
activate infected quiescent cells which might increase HIV
replication. Whether this really happens or not in people has not been
studied (quelle surprise). And indeed, any increase in immune response
may aid in the identification and elimination of infected cells rather
than increased viral activity.
This underscores the need for a holistic approach to developing a
complete program based on your current condition. The art of healing
goes way beyond just "take these pills!" Thus, the best time to start
replenishing glutathione levels is early on. For more advanced disease
or high viral load, it may be advisable to undertake GSH-replenishing
programs along with combination antiretroviral therapy (nukes and
protease inhibitors). The loss of this critical group of sulfur amino
acids (mainly cysteine, which is the building block used in the
manufacture of GSH) alters the host defense and results in significant
disease progression (Staal in Lancet, 1992). Therefore, DAAIR strongly
feels that replenishing glutathione levels is essential to survival
and far outweighs the hypothetical increase in HIV load.
Proliferation (or increase in numbers) of lymphocytes will not occur
if there is not enough glutathione inside the cell (Hamilos, 1989).
Hamilos notes that "Resting human lymphocytes are gradually depleted
of GSH over several days [in the presence of the glutathione inhibitor
BSO], whereas macrophages and mitogen-activated lymphocytes are
depleted of GSH within 24 hours" (Hamilos, 1992). Given the dynamic
battle waged between the immune system and HIV, it is little wonder
that GSH levels are lost. And as they are lost, the ability of T-cells
to appropriately proliferate is diminished. Indeed, Hamilos further
notes that "…lymphocytes appear to become progressively more dependent
upon GSH as the activation process proceeds." It is important to note
that even when IL-2 was added to the cultures, the
glutathione-depleted cells still did not respond even though they were
capable of synthesizing IL-2 as well (Hamilos, 1991). May this be a
clear warning to all those physicians and researchers exploring
cytokine-based immune upregulation/modulation in HIV infection;
ignoring the role of glutathione may jeopardize the outcome of such
treatments! Beside increased HIV production, people with lower T-cells
may have seen no increase in CD4 counts because they had insufficient
stores of intracellular glutathione. A study combining
antiretrovirals, low-dose IL-2 and OTC (or NAC) in people with low
T-cell might be warranted.
As has been discussed in the Comprehensive Goals and elsewhere, there
is a model, supported by a good deal of evidence from a wide variety
of sources, of how HIV causes AIDS. Part of this model centers around
the observation that there are still a lot of uninfected CD4+ T cells
dying. Indeed, an important part of the whole process has to do with
infection of the monocytes and macrophages that may be the primary
culprits in misdirected signals to the T cells. At the same time, the
body is in some ways over reacting to the HIV infection, resulting in
immune hyperactivation.
As mentioned above, excess free radicals due to the lack of sufficient
levels of GSH, turn on inflammatory (acute-phase response) genes
inside of cells. This is reflected in part in the increased levels of
cytokines like TNF-alpha and IL-6 as well as excessive antibody
production (evidenced by a lot of a particular type, IgG, known as
hypergammaglobulinemia). These cytokines in turn activate more T
cells, and this is happy news for the HIV infecting these activating T
cells: the process of activation results in increased HIV production.
At the same time, it causes yet more damage to uninfected cells and
local tissues. As the inflammatory molecules are released, the already
low levels glutathione needed to mop up the damage vanish and this
"acute phase response" goes unchecked (see the Comprehensive Goals
section on this topic). Energy producing mitochondria may be damaged,
reducing the supply of ATP which has the consequence of preventing the
synthesis of more glutathione (a situation exacerbated by AZT and
other nukes). Overall it is a vicious cycle. How to disrupt it? Two
ways: one, reduce viral load. Second is to do all those things that
provide the body the fuel it needs to synthesize glutathione and other
antioxidants and heal damage to tissues.
Thus, with low GSH, the excess free radicals which are generated trap
the body in a sustained "acute phase response" with associated
cellular activity stuck in hyperdrive along with HIV production. This
is the foundation of the host defense model of properly managing HIV
infection in a sustainable manner that goes beyond simply thwacking
the virus with highly toxic and often glutathione-depleting drugs.
Detoxification
Given the many very toxic drugs people with HIV often take for years,
it is important to understand a little bit about the role of
glutathione in detoxifying their undesirable by-products. To begin
with, glutathione, as has been mentioned, is one of the most prevalent
peptides in the body. Indeed, Lomaestro, citing several groups of
researchers, states "…GSH provides the bulk of available sulfhydryl
groups for binding and detoxification of reactive endogenous and
exogenous compounds such as peroxides and electrophiles (Lomaestro,
1995). (Electrophiles here refers to electron-loving molecules which
may be generated by pharmaceutical drugs. Endogenous means produced
from within, while exogenous refers to administration from outside;
for example, your body makes its own endogenous IL-2, but you can take
an exogenous infusion of it.)
The liver is the first stop on the road of orally consumed drugs. It
is not surprising to learn, then, that the liver is also a major organ
of glutathione production. Indeed, the liver also exports a great deal
of glutathione into the plasma. About 40% of the glutathione exported
by the liver is taken up by the lungs, heart and brain. The remaining
60% goes to the kidney, another important part of the detoxification
pathway (Deneke, 1989). Thus, it is extremely important to pay strict
attention to liver function, aiding it in as many ways as is possible
(including reducing or eliminating alcoholic beverages from the diet),
not only to protect its vital function but thereby to aid kidney,
lung, brain and intestinal functional, all targets of HIV destructive
capacity.
The liver needs to be well supported since GSH goes out from there to
other tissues. This does not mean that 100% of liver glutathione is
exported, of course. However, some tissues are dependent on GSH from
the liver. Liver is a synthesizer and user of glutathione but ALSO a
net exporter since it has low transpeptidase activity (in contrast to
the lung and intestinal epithelia which have high transpeptidase
activity). The transpeptidase enzymes helps with the import and export
of glutathione. Thus, if the liver is impaired, bodywide reductions in
GSH may result, with particular emphasis in certain compartments like
the lung and intestines (Taylor, 1996). It is worthwhile to note that
many infections suffered by PWHIV are concentrated in areas most
susceptible to glutathione depletion: lungs, GI tract, CNS, heart,
eyes.
Part of the mercapturate pathway (described above) is involved in
clearing the toxic byproducts produced when the body metabolizes
drugs. These toxic metabolites form "conjugates" with a family of
enzymes known as glutathione S-transferases (GSTs) (you’ve heard of
conjugal visits in prison? You get the idea…). This family,
prosaically named alpha, mu, pi, theta and other Greek alphabet
letters, is responsible for detoxification of carcinogenic and other
dangerous chemicals the body may encounter (Lomaestro, 1995; Meister,
1983). The S-transferases are also found in high quantities in the
liver, one of the major organs for detoxification. While the various
members of the cytochrome P450 enzyme system are critical for
metabolizing drugs, the GST pathway helps remove the toxic
by-products, as well as for liver disease in hepatitis (Fernandes,
1996), aflatoxin-induced liver cancer (Chen, 1996) and so forth. (But
sometimes these conjugates can be toxic themselves or may offset the
effects of some cancer chemotherapies, particularly cisplatin and
alkylating agents; Schroder, 1996). Please review the articles on
Detoxification in MOP.
Other studies suggest that not only does the sulfur group play an
important role, but also GSH utilizes its carboxyl group for binding
to various transferases (Widersten, 1996). Again, the effectiveness of
drugs is enhanced if their side effects are minimized. To the extent
that replenishing bodily stores of glutathione can do this, in
addition to its other immune modulatory functions, GSH replenishment
strategies should be considered an adjunctive therapy for many of the
antiviral, prophylactic and other pharmaceutical regimens often used
by people with AIDS.
One important feature of glutathione (and more strongly, NAC) is that
it may act as a chelating agent. These are chemicals that help the
body eliminate toxic metals. Studies in mice showed that, while the
standard agent (EDTA) was somewhat more effective than NAC and
glutathione, they were also more toxic. "Efficacy" here was defined as
the number of mice surviving a dose of cobalt chloride that, without
intervention, would kill half the mice while other mice were given a
dose that would kill over 99 percent. EDTA and penicillamine were
found to be the strongest (as other research had shown) while
glutathione and NAC (and cysteine) were less powerful but effective in
chelating the cobalt (Llobet, 1985).
Antiviral Functions
There is minimal evidence that glutathione operates as a direct
antiviral against HIV. (Although there is evidence that NAC does—see
the Information Sheet on NAC). This does not mean that there are not
numerous indirect ways GSH might act as an antiviral. However, given
that it is the most widely found peptide in the human body and the
array of functions it has (Deneke, 1989), and the noted depletion in
many people with progressing disease (see above), it seems clear that
every effort must be exerted to replenish the store. The result will
be a better ability by the body to offset the damage caused by the
overly strong, inflammatory response. This in turn creates an
environment more restrictive to HIV growth, partly by dampening the
overexpression of some cytokines, modulation of inflammatory
prostaglandins (PGE2; see the Essential Fatty Acids Information
Sheet), as well as inhibiting other viruses which, like HIV, depend on
the free radical-sensitive NF-kB pathway for their activation and/or
increased replication.
Some of the minimal evidence derives from results of test tube (in
vitro) studies reported in 1991 show that glutathione, glutathione
ester and N-acetylcysteine (NAC) can all inhibit HIV (although NAC
worked best in this system). Even when cells were stimulated by
cytokines like TNF and IL-6 (see the Immunology Primer), GSH, NAC,
etc. prevented HIV expression. This was achieved in U1 cells which is
a monocyte-derived cell line. (Monocytes are the cells that engulf
pathogens and develop into a variety of cells called macrophages). The
activity of reverse transcriptase was significantly reduced by all
three compounds. The formation of new HIV proteins (by mRNA) was
inhibited somewhat by the two forms of GSH and much more strongly by
NAC (Kalebic, 1991). Such studies must be confirmed by studies in
people.
Regimens, as suggested below, that can help to replenish glutathione
in various bodily compartments may also have a direct impact on viral
load. Such a thesis is easily tested—if there were the political will
to answer such critical questions. Unfortunately, due to the fact that
most of these are unpatentable approaches, greed dictates the studies
conducted and the kind of information people have to make treatment
decisions. This is a serious indictment of the global health care
situation that is perfectly suited to activist intervention.
Studies (Laboratory, Animal, Human)
In vitro work on mouse lymphocytes shows that increased levels of GSH
inside the cells (intracellularly) enhanced lymphocyte activation
(Fidelus, 1986). This activation was induced by the presence of
mitogens, chemicals which are used for the purpose of activating
T-cells. In these experiments, they used the drug OTC
(L-2-oxothiazolidine-4-carboxylate) to help increase levels of GSH
inside cells. OTC is being investigated in clinical trials in humans
with HIV.
One disturbing note that must be considered. In a test tube study of
OTC and infected, resting PBMC and another study in mice stripped of
their immune systems who had a human immune system grafted in
(SCID-hu), administration of OTC induced an increase in HIV production
(Schwartz, 1996). This may have to do with the activation of cells and
the consequent increase of HIV replication in these cells. On the
other hand, given the evidence that uninfected cells are dying, we
must restore their functional ability. Still, this may suggest that,
particularly for people with lower T-cell counts, a combination of
antivirals and glutathione-enhancing strategies is warranted. And
again—the relevance of this model to humans in this experiment is not
definitive.
In a study of aging mice with autoimmune diseases, no decrease in GSH
levels was observed. They did notice that immune responsiveness was
reduced. However, when they increased the level of GSH in spleen by
adding OTC, immune responsiveness in splenic lymphocytes was improved.
They hypothesize that these contradictory data suggest that there are
two pools of GSH, one in the cytoplasm and another, smaller one used
by the "powerhouse" of the cell, the mitochondria (Fidelus, 1987).
Various animal studies have been conducted that underscore the value
of glutathione in protecting against oxidative injury. (See the TIP
section, Anti-Oxidant Therapies In The Treatment Of HIV Infection.)
Early work showed that specific cells of pig intestines actively took
up glutathione. The cells examined, the brush border membranes from
the jejunum, are cells that line the inside of the intestines called
villi—the little hairlike projections that help absorb nutrients as
food passes through the intestines (Linder, 1984). These villi become
stunted with progression of HIV disease (see the Antioxidants in HIV
section of TIP).
Rats were anesthetized and killed and tissue from their intestines was
analyzed in the presence or absence of oxidative stressors. When
glutathione was added, the cells took it up and were protected from
the deleterious effects of the oxidants (Lash, 1986; also Hagen TM
(same group), 1987). Gut function in people with HIV is seriously
compromised, so it is encouraging to note that, at least in this
system, cells of the intestines were protected from oxidative injury
when glutathione is supplied. In later studies, the group found
evidence that rat’s kidneys were similarly protected by glutathione
(Hagen, 1988). What effect, if any, increase of GSH in plasma through
oral administration might have for PWHIV is unknown.
It is clinically recognized that improving glutathione levels in lung
tissues can help offset the crisis induced by acetaminophen overdose
as well as alleviated the acute onset of adult respiratory distress
syndrome (ARDS). Other evidence suggests that the chronic condition of
idiopathic pulmonary fibrosis may be inhibited by
glutathione-regenerating consumption of NAC (Ruffmann, 1991). (See the
Information Sheet on NAC.)
One study assessed the effect of using an aerosolized form of
glutathione. They used 600 mg twice a day in 14 people. After 3 hours,
they found that there was a sustained elevation of GSH; in conjunction
with this increase, they noted an increase in the oxidized form of
glutathione, GGSG. This probably indicates the active need to clean up
seriously stressed lungs (Holroyd, 1993).
Glutathione tends to spare the body’s supply of methionine from being
converted into cysteine or other forms (Tateishi, 1982). In addition,
methionine has been studied for its effects on preventing glutathione
from getting out of cells (efflux). Several studies in vitro and in
rat and other animal models indicate that methionine does this
(Fernandez-Checa, 1990), however we don’t have data on whether this
happens in human tissues. A liver enzyme critical to that production,
cystathionase, must be operating at a high level to convert methionine
into cysteine and thence to glutathione (Moldeus, 1981). ...
Historical/Traditional Use
Very little direct use of glutathione is documented in humans. This
does not mean that small groups of PWHIVs have not tried various
methods of direct GSH supplementation (see below). We know much more
about how the body uses this compound, what happens to people who are
deficient but we have little data on the direct use of GSH to offset
disease. Suffice it to say that neither oral nor injected forms of GSH
provide more than a brief elevation of levels in the plasma that
disappear after a couple of hours (or possibly much less; see below).
There are a number of possible reasons why oral intake doesn’t "work."
First, many cell types do not have the ability to transport whole
glutathione. Others, like intestinal epithelial cells, do and to that
extent, such administration may be useful. Some concern exists that
digestive processes may destroy the glutathione before it gets there.
In addition, there is the possibility that the highly reactive nature
of the cysteine moiety may well result in the glutathione being
rapidly oxidized before it can get to cells that need it. Getting
glutathione increases in T-cells probably will not be achieved by oral
consumption of whole GSH. [A recent abstract, submitted but not yet
approved, of an industry study suggested that oral use of a 3 gram
dose of GSH did sustain an increased level of GSH inside cells; this
needs to be verified and the results reproduced.]
More later. Cites available on request.
Greg Nigh
This is a very quick reply. George, I've not had time to read the draft
you posted, but I will ASAP. Thank you.
There have been a few people state that GSH is not good taken internally,
as it does not get to the cell. I did some searches, and here are a few
articles of interest along these lines. Nothing new here, just some
relevant info.
More later.
Greg
Accession No.: 94283554.
Author: Meyer-A. Buhl-R. Magnussen-H.
Title: The effect of oral N-acetylcysteine on lung
glutathione levels in idiopathic pulmonary fibrosis [see
comments]
Source: Eur-Respir-J. 1994 Mar. 7(3). P 431-6.
Comment: Comment in: Eur-Respir-J. 1994 Mar. 7(3). P 427-8.
Journal Title: EUROPEAN RESPIRATORY JOURNAL.
Abstract: Idiopathic pulmonary fibrosis (IPF) is characterized by an
increased oxidant burden and by a deficiency of
glutathione, a major antioxidant, in the lung epithelial
lining fluid (ELF). Therefore, a rational therapeutic approach
is to reverse the imbalance between oxidants and antioxidants
in the lung by enhancing the antioxidant screen. With this
background, the aim of our study was to evaluate oral N-
acetylcysteine (NAC) as a strategy to augment lung
glutathione levels in patients with IPF. Concentrations
of total glutathione in bronchoalveolar lavage fluid
(BALF) were quantified spectrophotometrically, before and
following oral therapy with 3 x 600 mg NAC per day for 5 days,
in 17 nonsmoking patients with biopsy-proven IPF. The volume of
ELF recovered by BAL was determined using the urea method.
Pretherapy, total glutathione levels in ELF in IPF
patients were significantly less than normal (187 +/- 36 vs 368
+/- 60 microM), in contrast to levels in BALF (0.99 +/- 0.12 vs
1.18 +/- 0.19 microM). Following therapy with oral NAC,
glutathione levels in BALF were 1.54 +/- 0.24 microM (a
significant increase compared to pretherapy), whereas the
increase in ELF levels (319 +/- 92 microM) did not reach
significance. The therapy was well-tolerated, and all routine
clinical and bronchoscopic parameters remained unchanged. It is
thus feasible and safe to augment deficient lung
glutathione levels in patients with IPF; thereby,
potentially augmenting pulmonary antioxidant protection.
------------------------------------------------------------------------------
Accession No.: 93039865.
Author: de-Quay-B. Malinverni-R. Lauterburg-B-H.
Title: Glutathione depletion in HIV-infected patients: role of
cysteine deficiency and effect of oral N-acetylcysteine.
Source: AIDS. 1992 Aug. 6(8). P 815-9.
Journal Title: AIDS.
Abstract: OBJECTIVE: To determine whether a single oral dose of N-
acetylcysteine corrects the deficiency of cysteine and
glutathione in plasma and mononuclear cells of HIV-
infected patients. DESIGN: Pharmacokinetic and pharmacodynamic
study. METHODS: Cysteine and glutathione were measured
in plasma and peripheral blood mononuclear cells of patients at
different stages of HIV infection before and after a single
oral dose of N-acetylcysteine. RESULTS: At baseline, the
plasma concentrations of glutathione and cysteine were
significantly lower in HIV-infected patients than in healthy
controls. The intracellular concentration of glutathione
correlated with the absolute CD4 lymphocyte counts: the
concentration of glutathione in mononuclear cells was
significantly lower in patients with more advanced
immunodeficiency. A single oral dose of N-acetylcysteine
increased the concentration of cysteine in plasma and
mononuclear cells of HIV-infected patients. Four hours after
N-acetylcysteine administration, intracellular
glutathione concentrations in the patients were
moderately higher than at baseline and at 2 h. CONCLUSIONS:
Oral N-acetylcysteine transiently increases the
concentrations of cysteine and glutathione in
mononuclear cells of patients with HIV infection. A sustained
increase in intracellular cysteine may be necessary to
normalize intracellular glutathione. This may be
accomplished by repeat administration of N-
acetylcysteine.
------------------------------------------------------------------------------
James Scutero
In article <Pine.SOL.3.91.97031...@enuxsa.eas.asu.edu>
>For those more familiar with the use and research on NAC, a question:
>
>antioxidant, do those who receive NAC as a therapy for immune suppression
>also receive supplemental GSH?
>
>reference to HIV+ patients only refer low levels of *reduced* GSH? What
>I'm getting at is that the effectiveness of NAC seems like it might be
>dependent upon the presence of non-reduced GSH, so that *if* glutathione
>is not supplemented along with NAC therapy, there may not be enough GSH
>around for NAC to *keep* reduced.
>
>Any thoughts?
>
Garlic supplies GSH, increases GSH peroxidase activity and
increases intracellular GSH levels. Garlic is inexpensive, highly
biolavailable, and is grown all over the world. It's great with pasta.
Cancer Biochem Biophys 8: 299-312 (1986)[87102529]
Effects of garlic and onion oils on glutathione peroxidase activity, the ratio
of reduced/oxidized glutathione and ornithine decarboxylase induction in
isolated mouse epidermal cells treated with tumor promoters.
J. P. Perchellet, E. M. Perchellet, N. L. Abney, J. A. Zirnstein & S.
Belman
Garlic oil, onion oil and one of its constituents, dipropenyl sulfide,
all increase, to diverse degrees, glutathione (GSH) peroxidase
(GSH:H2O2 oxidoreductase, EC 1.11.1.9) activity in isolated epidermal
cells incubated in the presence or absence of the potent tumor
promoter 12-0-tetradecanoylphorbol-13-acetate (TPA). The stimulatory
effects of these oils on epidermal GSH peroxidase activity are
concentration-dependent and long-lasting, and thus, abolish totally
the prolonged inhibitory effect of TPA on this enzyme. Moreover,
garlic oil (5 micrograms/ml) inhibits by about 50% TPA-induced
ornithine decarboxylase (ODC, L-ornithine carboxy-lyase, EC 4.1.1.17)
activity in the same epidermal cell system. This concentration of
garlic oil also increases remarkably GSH peroxidase activity and
inhibits ODC induction in the presence of various nonphorbol ester
tumor promoters. Since the same oil treatments inhibit dramatically
the sharp decline in the intracellular ratio of reduced (GSH)/oxidized
(GSSG) glutathione caused by TPA, it is suggested that some of the
inhibitory effects of garlic and onion oils on skin tumor promotion
may result from their enhancement of the natural GSH-dependent
antioxidant protective system of the epidermal cells.
* * *
-Giacomo
Giacomo's Cabaret, http://www.panix.com/~jscutero
George M. Carter
jscu...@panix.com (James Scutero) wrote:
> Garlic supplies GSH, increases GSH peroxidase activity and
>increases intracellular GSH levels. Garlic is inexpensive, highly
>biolavailable, and is grown all over the world. It's great with pasta.
The extract, Allicin, was shown to have significant activity against
cryptosporidiosis. Some people had some unpleasant side effects from
that. My guess is that the garlic is supplying selenium that is
utilized by the GPx. Other nutrients that might replenish glutathione
levels include NAC, alpha lipoic acid and whey. Vitamins (B6, C, E)
and selenium can also be useful to that end.
George M. Carter
James Scutero
In article <5h0k28$g...@dfw-ixnews6.ix.netcom.com> gm...@ix.netcom.com writes:
>jscu...@panix.com (James Scutero) wrote:
>
>> Garlic supplies GSH, increases GSH peroxidase activity and
>>increases intracellular GSH levels. Garlic is inexpensive, highly
>>biolavailable, and is grown all over the world. It's great with pasta.
>
>The extract, Allicin, was shown to have significant activity against
>cryptosporidiosis. Some people had some unpleasant side effects from that.
>
Allicin has been reported to have cleared crypto in severely
immune compromised individuals (see "garlic" http://www.panix.com/~jscutero),
but that's not what is credited with the increases in intracellular GSH
in the studies that were cited here. The published side-effects of
allicin in the crypto trial included a strong garlic taste and smell.
Allicin is a sulphur compound found in fresh garlic that is produced when
garlic is crushed or cut. Alliin and allinase in garlic combine to produce
allicin. Allicin is very unstable and has a half-life of a few hours.
Consequently, garlic that is prepared and stored, as in the form of garlic
oil, does not contain much, if any, allicin. (See Heinerman, J., The
Healing Benefits of Garlic., New Canaan, Conn., Keats, 1994). Again,
allicin is not a garlic compound that was reported to be responsible for
raising intracellular GSH levels in the studies that were cited here. Aged
garlic extract and garlic oil were the substances that were studied.
Carter is confused in the allicin wonderland.
This cite discussed aged garlic extract (low to no allicin):
On Mon, 24 Feb 1997 13:45:39 -0700,
in message <Pine.SOL.3.91.97022...@enuxsa.eas.asu.edu>,
Greg Nigh <gn...@enuxsa.eas.asu.edu> writes,
>Citation: Geng and Lau. "Aged Garlic Extract Modulates Glutathione Redox
>Cycle and Superoxide Dismutase Activity in Vascular Endothelial Cells."
>Phytotherapy Research Vol. 11: 54-56 (1997).
>
>Abstract:
>
>"In this study the effect of an aged garlic extract (AGE) on glutathione
>(GSH) redox cycle and activity of antioxidant enzymes was investigated.
>Confluent monolayers of bovine pulmonary artery endothelial cells (PAEC)
>were incubated with varying concentrations of AGE for 8-48 h, washed, and
>then lysed with Triton X-100. Biochemical assays were performed with
>the lysate. AGE caused both dose- and time-dependent increases in
>intracellular GSH level, glutathone disulphide (GSSG) reductase and
>superoxide dismutase (SOD) activity while GSSG level was decreased. These
>results suggest that the antioxidant effect of AGE may be due to its
>modulation of the GSH redox cycle and SOD activity in vascular
>endothelial cells."
And this cite discussed garlic oil (low to no allicin):
In message-id <5guvn3$7...@panix.com>, jscu...@panix.com (James Scutero)
writes:
Here are the reported side-effects of allicin. No other treatment
for crypto has been reported to be as effective as allicin.
_________________________________________________________________
Garlic for cryptosporidiosis? Clearinghouse, AIDS Newsletter Database,
P.O. Box 6003, Rockville, MD 20849-6003. 800-458-5231 ext. 5714.
Treat Rev. 1996 Aug;(No 22):11. Unique Identifier : AIDSLINE
AIDS/96701909
_________________________________________________________________
Abstract:
The AIDS Research Alliance in California has been testing the
effectiveness of garlic in combating cryptosporidiosis, a parasitic
infection of the intestinal tract. The test involved patients taking
liquid Allicin mixed with distilled water twice daily. Side effects
included the expected garlic taste and smell, but patients suffered
from less diarrhea and had stable or increasing body weight. For
several patients, repeated testing showed negative results for
cryptosporidium parasites. Larger trials are planned.
_________________________________________________________________
Keywords: AIDS-Related Opportunistic Infections/*DRUG THERAPY
Anti-Infective Agents/ADVERSE EFFECTS/*THERAPEUTIC USE
Cryptosporidiosis/*DRUG THERAPY *Garlic Human Sulfinic Acids/ADVERSE
EFFECTS/*THERAPEUTIC USE NEWSLETTER ARTICLE
SOURCE: National Library of Medicine. NOTICE: This material may be
protected by Copyright Law (Title 17, U.S.Code).