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AO
Übersetzungsvorlage Nummer 1
Original veröffentlicht von Rich van Konynenburg
How does the Glutathione Depletion—Methylation Cycle Block (GD-MCB) Hypothesis explain other aspects of chronic fatigue syndrome?
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Quelle: Glutathione and Methylation in and chronic fatigue syndrome (ME/CFS)
AO
Übersetzungsvorlage Nummer 1
Original veröffentlicht von Rich van Konynenburg
How does the Glutathione Depletion—Methylation Cycle Block (GD-MCB) Hypothesis explain other aspects of chronic fatigue syndrome?
Damit die Zahlen nicht irritieren: Alle Zahlen in Klammern beziehen sich auf die Quellenangeben im Originaltext.
Ich setzte fette Zahlen vor die bereits im Original gegliederten Stellen.
Wenn jemand mit der Übersetzung beginnt, bitte kurz posten, dass nun von Übersetzungsvorlage 1 Abschnitt xy übersetzt wird.
Vielen Dank und viele Grüsse - tiga!!!
1.1
How does the Glutathione Depletion—Methylation Cycle Block (GD-MCB) Hypothesis explain other aspects of chronic fatigue syndrome?
Etiology: According to the GD-MCB Hypothesis, CFS is caused by a combination of two factors:
(1) a genetic predisposition (87), which is currently only partly known, and
(2) some combination of a variety of physical, chemical, biological and/or psychological/emotional stressors, the particular combination differing from one case to another (See Ref. 1 for a review.).
So far, polymorphisms in genes coding for the following proteins have been found to be associated with CFS in general or with a subset:
(1) Serotonin transporter (5-HTT) gene promoter (88)
(2) Corticosteroid binding globulin (CBG) (89)
(3) Tumor necrosis factor (TNF) (90)
(4) Interferon gamma (IFN-gamma) (90)
(4) Proopiomelanocortin (POMC) (91)
(5) Nuclear receptor subfamily 3, group C, member 1, glucocorticoid receptor (66,91)
(6) Monoamine oxidase A (MAO A) (91)
(7) Monoamine oxidase B (MAO B) (91)
(8) Tryptophan hydroxylase 2 (TPH2) (66,91)
(9) Catechol-O-methyltransferase (COMT) (66)
How does the GD-MCB Hypothesis explain other aspects of chronic fatigue syndrome?
In addition, a COMT polymorphism has reported to be associated with fibromyalgia (92, 93), and polymorphisms in the genes for the detoxication enzymes CYP2D6 (cytochrome P450 2D6) and NAT2 (N-acetyl transferase 2) have been found to be associated with multiple chemical sensitivities (94). These may be relevant to CFS because of its high comorbidities with these two disorders.
All these proteins touch on the pathogenesis mechanism described in this paper, which is what would be expected if this Hypothesis is valid.
With regard to the stressors found to precede onset of CFS, they are known to raise cortisol secretion (prior to onset and early in the course of the illness), to raise epinephrine secretion and to place demands on glutathione, leading to oxidative stress (1).
According to this Hypothesis, when reduced glutathione is sufficiently depleted and the oxidative stress therefore becomes sufficiently severe in a person having the appropriate genetic predisposition, a block is established at methionine synthase in the methylation cycle (95,2,3). Because the methylation cycle is located upstream of cysteine and glutathione in the sulfur metabolism, these are further depleted, and a vicious circle is formed.
1.2How does the GD-MCB Hypothesis explain other aspects of chronic fatigue syndrome?
Note that infectious pathogens are included among the possible biological stressors that can contribute to the onset of CFS. In particular, Borrelia burgdorferi, the bacterium responsible for Lyme disease, has been found to deplete glutathione in its host (96). This may explain the very similar pathophysiologies of chronic Lyme disease and CFS. This may also explain the epidemic clusters of CFS, which seem to have been produced by a virulent infectious pathogen (or pathogens). Perhaps the genetic factors are less important in producing the onset if a very virulent pathogen is present.
Epidemiology: According to the GD-MCB Hypothesis, the prevalence of CFS is determined by the frequency in the population of the combined presence of certain genetic polymorphisms (yet to be completely identified) and of the above described stressors occurring coincidentally in those having the polymorphisms. As noted earlier, the author has proposed that the higher prevalence in women is a result of increased bias toward oxidative stress, resulting from redox cycling in the metabolism of estradiol when certain polymorphisms in detoxication enzymes are present (76).
Suppression of parts of the immune response: Elevation of cortisol due to long-term stressors causes a suppression of the cell-mediated immune response and a shift to Th2 (97).
1.3How does the GD-MCB hypothesis explain other aspects of chronic fatigue syndrome?
Depletion of reduced glutathione likewise causes a shift to Th2 (98, 99).
The elevation of cortisol prior to onset and in the early course of the illness also (temporarily) suppresses inflammation (100).
The cytotoxicity of natural killer (NK) cells and CD8 T cells in CFS has been found to be low, and Maher et al. found this to be associated with a deficiency of perforin secretion (101). According to the GD-MCB Hypothesis, in CFS perforin secretion is inhibited by depletion of reduced glutathione because glutathione is needed to form the disulfide bonds in their proper configurations in secretory proteins (102). Depletion of glutathione therefore causes misfolding and recycle of perforin molecules, which have twenty cysteine residues and thus ten disulfide bonds (103). This misfolding mechanism would affect other secretory proteins in CFS that are synthesized in cells having glutathione depletion as well, which may account for the observation of misfolded proteins in the spinal fluid of CFS patients by Baraniuk et al. (104).
Proliferation of T lymphocytes is inhibited by the block in the folate cycle, which inhibits production of new RNA and DNA (105).
1.4How does the GD-MCB Hypothesis explain other aspects of chronic fatigue syndrome?
Viral and intracellular bacterial reactivation: According to the GD-MCB Hypothesis, depletion of reduced glutathione is the trigger for the reactivation of latent viral and intracellular bacteria in CFS. The infections found initially in a case of CFS are usually due to those pathogens that are capable of residing in the body in the latent state, suggesting that these infections arise by reactivation (106). In general, intracellular glutathione depletion is associated with the activation of several types of viruses (1, 107-111) as well as Chlamydia (112), and it may account for reactivation of other latent intracellular bacteria as well. In herpes simplex type 1 viral infection, raising the glutathione concentration inhibits viral replication by blocking the formation of disulfide bonds in glycoprotein B (111). Since glycoprotein B appears to be present in all herpes virus types (113), it is likely that glutathione depletion is responsible for reactivation of Epstein-Barr virus, cytomegalovirus and HHV-6 in CFS.
The Coxsackie B3 virus genome is known to code for glutathione peroxidase, a selenium-containing enzyme (114). Taylor has suggested (115) that such viruses suppress the immune system of the host by depleting its selenium, thus inhibiting the host’s use of glutathione peroxidase. Since glutathione peroxidase makes use of
1.5How does the GD-MCB Hypothesis explain other aspects of chronic fatigue syndrome?
glutathione, depletion of reduced glutathione itself would therefore assist this virus in its mechanism of infection.
Populations more deficient in selenium would be expected to be more vulnerable to Coxsackie B3 infection. It is interesting to note that nearly all the studies of Coxsackie virus in CFS have come from the UK. The population there has become more deficient in selenium since the 1970s, when major sources of grain in the diet were changed to areas with selenium-deficient soils (116).
Immune activation: This occurs when the immune system detects the reactivation of pathogens (117).
Activation of 2-5A, RNase-L pathway (118): This pathway is activated by interferon and double stranded RNA as part of the cellular response to viral reactivation. According to the GD-MCB Hypothesis, RNase-L remains activated in CFS because of the suppression of the cell-mediated immune response and the consequent failure to defeat the viral infection (See "Suppression of parts of the immune response," above.)
Mitochondrial dysfunction and the onset of physical fatigue: As hypothesized by Bounous and Molson (119), competition between the oxidative skeletal muscle cells and
1.6How does the GD-MCB Hypothesis explain other aspects of chronic fatigue syndrome?
the immune system for the decreased supply of glutathione and cysteine causes depletion of reduced glutathione in the skeletal muscles. According to the GD-MCB Hypothesis, this inhibits the glutathione peroxidase reaction and allows hydrogen peroxide to build up. This in turn probably exerts product inhibition on the superoxide dismutase reaction, which allows superoxide, produced as part of normal oxidative metabolism, to rise in the mitochondria of the oxidative skeletal muscle cells. Superoxide reacts with nitric oxide to produce peroxynitrite, as Pall (120) has pointed out. Superoxide also interacts with aconitase in the Krebs cycle to inhibit it (121), and peroxynitrite can cause partial blockades in the Krebs cycle and also the respiratory chain (120, 122). These reactions lower the rate of production of ATP, and this constitutes mitochondrial dysfunction. Since ATP is needed to power muscle contraction, lack of it produces physical fatigue.
RNase-L cleavage, leading to formation of the low molecular weight version (123): Depletion of reduced glutathione removes inhibition of the activity of calpain (124), which is located in the cytosol with RNase-L, and calpain cleaves RNase-L (125). (Elastase, the other enzyme found by Englebienne et al. (125) to be able to cleave RNase-L in the laboratory, is confined to granules and vesicles inside living cells (126), and thus is not in contact with RNase-L.)
1.7How does the GD-MCB Hypothesis explain other aspects of chronic fatigue syndrome?
Failure to defeat viral and intracellular bacterial infections and continuing immune activation: According to the GD-MCB Hypothesis, these occur because of depletion of reduced glutathione (127) and also because the folate metabolism block prevents production of new DNA and RNA for proliferation of T lymphocytes (105).
Depletion of magnesium: There is a long history showing depletion of magnesium in CFS and benefits of supplementation, both orally and by injection (See review in Ref. 39). Magnesium depletion may be responsible for a variety of symptoms that are found in CFS (128), including mitochondrial dysfunction, muscle twitching, muscle pain, sleep problems and cardiac arrhythmia. In connection with sleep problems, Durlach et al. have found that magnesium depletion is associated with abnormalities in the level of melatonin and dysregulation of biorhythms (129). Manuel y Keenoy et al. (54) found that the subset of CFS patients that was resistant to repletion of magnesium in their clinical study also showed glutathione depletion. It has also been found that glutathione depletion causes magnesium depletion in red blood cells (130). According to the GD-MCB Hypothesis, the depletion of intracellular magnesium in CFS is another result of depletion of reduced glutathione.
Buildup of toxins: Glutathione depletion allows toxins, including heavy metals, to build up, because there is not
1.8How does the GD-MCB Hypothesis explain other aspects of chronic fatigue syndrome? (continued)
enough glutathione to conjugate these toxins as rapidly as they enter the body. Mercury is of particular concern, because the population in general has considerable exposure to it from dental amalgams, fish consumption, and environmental sources such as nearby coal-fired power plants. There is considerable clinical experience of mercury buildup in CFS patients (1). Immune testing has also shown evidence that the immune system has responded to elevated mercury in CFS patients (131-133).
Solidification of the vicious circle: After the vicious circle has developed involving the methylation cycle block and the depletion of glutathione, another factor must come into play to lock in this situation chronically. It seems likely that buildup of toxins is the factor responsible for this, by blocking the formation of methylcobalamin and thus the activity of methionine synthase. It has been shown that one of the important roles of glutathione normally is to protect the very much smaller (by six orders of magnitude) concentrations of cobalamins from reaction with toxins by forming glutathionylcobalamin (134). Without this protection, cobalamins are vulnerable to reaction with a variety of toxins. An example is mercury. It has been found that very small concentrations of mercury are required to block the methionine synthase reaction (135). Because of this additional factor, attempts simply to correct the glutathione depletion and the oxidative stress after the
1.9How does the GD-MCB Hypothesis explain other aspects of chronic fatigue syndrome? (continued)
cobalamins have reacted with toxins in most cases will not restore normal function of the methylation cycle (1).
Neurotransmitter dysfunction: The production of melatonin from serotonin as well as the metabolism of the catecholamines require methylation, as noted earlier, and according to the GD-MCB Hypothesis, they are inhibited because of the decreased methylation capacity. Also, genetic polymorphisms involving enzymes in the neurotransmitter system have been found to be more frequent in at least some subsets of CFS patients, as noted earlier. These factors cause dysfunction of the neurotransmitters.
Further development of mitochondrial dysfunction: As the course of the illness progresses, it is likely that other factors that result from glutathione depletion and the methylation cycle block come into play and further suppress the operation of the mitochondria. These include the buildup of toxins and infections, depletion of magnesium, and damage to the phospholipid membranes of the mitochondria by oxidizing free radicals (136). Because the essential fatty acids in these membranes are polyunsaturated, they are the most vulnerable to oxidation (137), and they become depleted, at least in some CFS patients (See review in Ref. 39).
1.10How does the GD-MCB Hypothesis explain other aspects of chronic fatigue syndrome? (continued)
HPA axis blunting (138): According to this Hypothesis, glutathione depletion in the pituitary gland inhibits production of proopiomelanocortin (POMC) (which has
two disulfide bonds in its N-terminal fragment (139)), and hence secretion of ACTH (which is part of POMC), by the same mechanism as inhibition of perforin synthesis (102) (See "Suppression of parts of the immune response," above.). This results in the lowering of cortisol secretion by the adrenal glands, which is a late finding in the course of the illness (140). As noted earlier, genetic polymorphisms in POMC may also be involved in a subset of CFS patients (91).
Diabetes insipidus (excessive urination, thirst, decrease in blood volume): According to this Hypothesis, glutathione depletion inhibits production of arginine vasopressin (141), which has one disulfide bond (142), by the same biochemical mechanism by which it inhibits perforin and ACTH synthesis (102). It is likely that the secretion of oxytocin, which also has one disulfide bond and is also synthesized in the hypothalamus, is also inhibited. Measurements of oxytocin in CFS have not been reported, but there is evidence that it is low in some fibromyalgia patients (143), which may be relevant because of the high comorbidity of CFS and fibromyalgia. A clinician has reported benefit from oxytocin injections in fibromyalgia patients (144).
1.11How does the GD-MCB Hypothesis explain other aspects of chronic fatigue syndrome? (continued)
Low cardiac output (145): According to this Hypothesis, this occurs because depletion of reduced glutathione in the heart muscle cells lowers the rate of production of ATP, as in the skeletal muscle cells. This produces diastolic dysfunction as observed by Cheney (146, 147). Both low blood volume (see Diabetes insipidus, above), which produces low venous return, and diastolic dysfunction, which decreases filling of the left ventricle, produce low cardiac output. In addition, in some cases, as observed by Lerner et al., viral infections produce cardiomyopathy (148). According to the GD-MCB Hypothesis, this is a result of depletion of reduced glutathione and suppression of cell-mediated immunity. This is another factor that can decrease cardiac output in CFS.
Orthostatic hypotension and orthostatic tachycardia (149): According to this Hypothesis, these occur because of low blood volume, low cardiac output and HPA axis blunting (See Diabetes insipidus, Low cardiac output, and HPA axis blunting, above.).
Loss of temperature regulation: As pointed out by Cheney (146), this occurs because of low cardiac output (see Low cardiac output, above), which causes the autonomic nervous system to decrease blood flow to the skin. This removes the ability to regulate the rate of heat loss from the skin.
1.12How does the GD-MCB Hypothesis explain other aspects of chronic fatigue syndrome? (continued)
Hashimoto’s thyroiditis (150) and elevated incidence of thyroid cancer (151): According to this Hypothesis, Hashimoto’s thyroiditis occurs in CFS because depletion of reduced glutathione in the thyroid gland allows damage to thyroglobulin by hydrogen peroxide, as proposed by Duthoit et al. (152). In addition, hydrogen peroxide damage to DNA in the thyroid gland may be responsible for the elevated incidence of cancer there. Hydrogen peroxide is produced normally by the thyroid to oxidize iodide in the process of making thyroid hormones (153).
Increasing variety of infections (154) and inflammation (155): According to this Hypothesis, viral, intracellular bacterial and fungal infections accumulate over time because the cell-mediated immune response is dysfunctional (See "Suppression of parts of the immune response," above.). Inflammation becomes more severe because of the decreased secretion of cortisol later in the course of the illness (See "HPA axis blunting," above), and because of the rise in histamine as a result of lack of sufficient methylation capacity to deactivate it (156).
Slow gastric emptying (157) and gastroesophageal reflux: According to this Hypothesis, in CFS these result from mitochondrial dysfunction in the parietal cells of the
1.13How does the GD-MCB Hypothesis explain other aspects of chronic fatigue syndrome? (continued)
stomach, due to depletion of reduced glutathione, which results in low production of stomach acid. (Anecdotally, many CFS patients have reported absence of eructation after ingestion of sodium bicarbonate solution on an empty stomach, suggesting low stomach acid status.) A slower rate of gastric emptying was found to be associated with higher pH, i.e. lower acid status (158).
Gut problems: According to this Hypothesis, several of the above factors converge to produce problems in the gut in CFS, often referred to as irritable bowel syndrome (IBS). These factors include glutathione depletion, low cardiac output, immune suppression, low stomach acid production, neurotransmitter dysfunction (note that serotonin plays a major role in gut motility), and increasing variety of infections and inflammation.
The degree of abnormality of a lactulose breath test (indicating small intestinal bacterial overgrowth) in fibromyalgia patients was found by Pimentel et al. to be greater than in IBS patients without fibromyalgia (159). In addition, they found that the abnormality was correlated with somatic pain (159). (This may be relevant because of the high comorbidity of CFS with fibromyalgia.)
1.14How does the GD-MCB Hypothesis explain other aspects of chronic fatigue syndrome? (continued)
Brain-related problems: According to this Hypothesis, several of the above factors also converge to produce problems in the brain. These include glutathione (and cysteine) depletion, low cardiac output, failure to defeat infections and continued immune activation, neurotransmitter dysfunction, decreased methylation capacity to maintain myelin, and increasing variety of infections and inflammation.
Relapsing (Crashing) (160): Many CFS patients have chronically low glutathione levels. According to this Hypothesis, when the level of stressors is temporarily increased, the levels of reduced glutathione become more severely depleted, and this produces the so-called crashing phenomenon. After a period of rest, reduced glutathione levels are increased to the chronically low levels that existed prior to the increased stressors.
Alcohol intolerance (161): According to this Hypothesis, because of mitochondrial dysfunction, the skeletal muscles of CFS patients depend more than normal on glycolysis for ATP production. Increased use of glycolysis requires increased use of gluconeogenesis by the liver to convert lactate and pyruvate back to glucose (Cori cycle). In CFS, this is hampered by low cortisol levels. The metabolism of ethanol by the liver further inhibits gluconeogenesis,
1.15How does the GD-MCB Hypothesis explain other aspects of chronic fatigue syndrome? (continued)
producing hypoglycemia and lactic acidosis. This accounts for the alcohol intolerance reported by many CFS patients.
Weight gain: According to this Hypothesis, the weight gain often seen in CFS results from the inability to metabolize carbohydrates and fats at normal rates, because of partial
blockades in the Krebs cycle produced by depletion of reduced glutathione. Excess carbohydrates are cycled back to glucose by gluconeogenesis, and ultimately are converted to stored fat.
Low serum amino acid levels (19): According to this Hypothesis, these result from the burning of amino acids as fuel at higher rates than normal. Amino acids are able to enter the Krebs cycle by anaplerosis, downstream of the partial blockades, so they can be used as fuel in place of carbohydrates and fats.
The pathogenesis of CFS becomes increasingly complex as it proceeds, because of the interactions and feedback loops that develop. For this reason, determining the cause-effect relationships for all the aspects of the resulting pathophysiology is a problem that is exceedingly difficult. Nevertheless, understanding the etiology and early pathogenesis provides a basis for developing a more effective treatment approach.
CONCLUSIONS
There is abundant and compelling evidence that the glutathione depletion—methylation cycle block mechanism is an important part of the pathogenesis for at least a substantial subset of chronic fatigue syndrome patients.
A pathogenesis hypothesis based on this mechanism is capable of explaining and unifying many of the published observations regarding chronic fatigue syndrome, and it provides a basis for developing a more effective treatment approach.
(A Yahoo discussion group is now devoted to these topics. You can find it at
CFS_Yasko : Dr. Amy Yasko CFS Treatment
Quelle: Glutathione and Methylation in and chronic fatigue syndrome (ME/CFS)
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