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5, 6, 7, 8, 9, 10, 11, 12
RATIONALE
FOR FIBROMYALGIA/CFS FATIGUE
It is well known that one of the major symptoms
of fibromyalgia is muscle fatigue, while general fatigue is more characteristic
of CFS.
Both of these responses may be explained at the biochemical level by
including fungi as a major contributory factor in the etiology of these
diseases.122
Cyclopiazonic Acid
One of the primary mycotoxins produced
by Aspergillus as well as Penicillium species is cyclopiazonic acid.
This toxin is also produced by species
of Fusarium and Alternaria.109 Cyclopiazonic acid is formed from
certain species of Penicillium, including P. roqueforti used in the
manufacture of Roquefort cheese (also known as "blue cheese").
Other blue-veined cheeses are Gorgonzola and Stilton.
The mechanism of action of cyclopiazonic
acid is illustrated in Figure
7.(15KB .pdf) In muscle cells, the calcium required for muscle
contraction is held in a subcellular organelle or compartment known
as the sarcoplasmic
reticulum (SR). There are two kinds of receptors (calcium pumps) found
in the bilayer lipid membrane surrounding this storage. One is the
receptor for inositol triphosphate (IP3), mentioned previously in relation
to the pain mechanism. IP3, which, when bound to its receptor on the
SR, allows the efflux of calcium into the cytosol and eventually results
in muscle contraction. Once released into the cytosol, calcium must
be returned to the SR storage chamber through a second type of calcium
pump. This process requires energy and employs an ATP-driven pump known
as Ca+2-ATPase because of its consumption of ATP (the energy
molecule). Cyclopiazonic acid inhibits the activity of this pump, allowing
an
accumulation of calcium in the cytosol.110
The IP3 receptor that releases calcium from
the SR into the cytosol is activated by adenophostins A and B (agonists).
These mycotoxins
are produced by Penicillium brevi-compactum and consist of phosphorylated
adenine (found in one of the units of RNA/DNA). These substances mimic
the action of inositol triphosphate (IP3) and are 100 times more effective
in releasing calcium from the SR.111 The net result of these
two mycotoxins (cyclopiazonic acid and adenophostins) is to increase
the calcium concentration
of the cytosol, having a damaging effect on the mitochondria.112 See
Figure 7 (15KB .pdf) and Figure
8. (16KB .pdf)
Cyclopiazonic acid has a negative effect
on cardiac muscle accompanied by marked prolongation of the contraction
duration,
probably through
inhibition of SR function.110 Radioactive cyclopiazonic acid was used as a tracer in a study to
determine the site of action of an administered dose. Skeletal muscle
tissue contained 48% of the radioactive dose six hours after either
ip or ig administration.113
Gliotoxin
Gliotoxin is a mycotoxin produced by Aspergillus fumigatus that
has immunosuppressive properties.120
Creatine is a simple organic substance
found abundantly in muscle. Creatine is capable of binding a phosphate
group and acting as a phosphate
donor to adenosine diphosphate (ADP), forming adenosine triphosphate
(ATP). Since muscles require ATP for muscle contraction, a quickly
available source of ATP in times of stress is greatly desirable.
Gliotoxin
inhibits creatine kinase, leading to lowered ATP and muscle fatigue.114
See Figure 9. (12KB .pdf)
In vitro treatment of splenocytes
with gliotoxin revealed relative decreases in CD4+ and increases
in CD8+ T-cells, similar to one characteristic
of AIDS.115
Chemistry of Cyclopiazonic Acid and Gliotoxin
If we look at Figure
11A (15KB .pdf),
which shows the chemical structures of cyclopiazonic acid and gliotoxin,
we might
ask why cyclopiazonic acid is called
an acid, since there are no carboxylic acid groups present. Two
structures
convey acidity to this molecule. The pyrrole ring (designated A)
contains two unsaturations that withdraw electrons from the nitrogen
atom, thereby
making it more positive and repelling the hydrogen atom (proton).
Ring C carries two carbonyl groups (C=O) and one ethylenic group
(C=C).
These unsaturated groups are electron-withdrawing in relation to
the sole hydroxy group (-OH), making the oxygen atom more positive
and
repelling the attached hydrogen atom (proton). The result of these
proton repulsions is to make either the oxygen of the –OH group
or the nitrogen of the =NH group (or possibly both) negatively charged.
An acid is a substance capable of releasing protons into solution.
The two methyl groups (-CH3)
attached to ring B are electron-contributing, making the tertiary nitrogen
(bound to three carbon atoms) shared by
fused rings B and C more basic (more able to bind a proton). Thus,
the protons liberated from either the –OH or the =NH groups are
capable of binding to the basic nitrogen shared by rings B and C, thereby
becoming a four-bonded nitrogen carrying a positive charge. This, combined
with the negative =N- or negative –O- atoms,
form what is known as an "internal salt" or zwitterions,
in which both the positive and negative charges of the salt are present
in the same molecule.
See Figure 11B.(14KB .pdf)
The presence of these charged groups on the same molecule enable cyclopiazonic
acid to have great affinity for the Ca+2-ATPase on the surface of the
SR and block its pumping action for the Ca+2 ion.110
The most significant chemical feature
of gliotoxin is the transannular disulfide linkage (-S-S-), also
explaining its mode of action. The
disulfide form shown in Figure 11A (15KB
.pdf) may be reduced, breaking the bond between the two sulfur atoms
and replacing
them by two –SH (sulfhydryl)
groups. In this form, either of the –SH groups may form a disulfide
linkage with a similar group in a protein, thereby inactivating the
protein (including enzymes).116 See
Figure 11C.(14KB .pdf)
Gliotoxin is also known to cause breaks in either single- or double-stranded
DNA.117
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