glutathione depleteion and stress vs. adrenaline & cortisol

[Guest guest]

IN THE GENERAL POPULATION, WHAT FACTORS OR CONDITIONS ARE KNOWN TO CAUSE

DECREASES IN INTRACELLULAR GLUTATHIONE CONCENTRATIONS?

<http://www.personalconsult.com/articles/glutathioneandchronicfatigue.html>

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These factors and conditions can be divided into three groups:

he first group is made up of those that (1) lower the rate of GSH synthesis or

the rate of reduction of GSSG to GSH, or (2) raise the rate of export of GSH

from cells, or (3) lead to loss of GSH from the scavenging pathway. This group

includes the following: genetic defects [15], elevated adrenaline secretion

[16-20] due to various types of stress, deficient diet [1] or fasting [21],

surgical trauma [21,22], burns [23], and morphine [24].

The second group is comprised of toxins that conjugate GSH and remove it from

the body [25], such as organophosphate pesticides, halogenated solvents, tung

oil (used on furniture), acetaminophen and some types of inhalation anesthesia.

The third group is comprised of conditions that raise the production rates of

reactive oxygen species high enough to produce oxidative stress, causing cells

to export GSSG. These include strenuous or extended exercise [26], infections

(producing leukocyte activation) [21], toxins that produce oxidizing free

radicals during Phase I detoxication by cytochrome P450 enzymes [21], ionizing

radiation [27], iron overload [28], and ischemia--reperfusion events (such as

stroke, cardiac arrest, subarachnoid hemorrhage, and head trauma) [29].

STRESS, DISTRESS, AND STRESSORS

For purposes of this presentation, stressors are defined in the broad sense as

events, circumstances or conditions that place demands on a person and tend to

move his or her body out of allostatic balance. Allostasis is similar to

homeostasis, but allows for changes in the set-point over time to match life

circumstances [30]. Stressors can be classified as physical, chemical,

biological, or psychological/emotional.

Stress is the state that results from the presentation of such demands. Selye

[31] defined stress as " the state manifested by a specific syndrome which

consists of all the nonspecifically-induced changes within a biologic system. "

Although Selye emphasized the nonspecifically-induced responses, the body also

exhibits specific responses that depend on the type of stress [32].

Stress can be of a beneficial or a destructive nature. Distress is the

destructive type of stress [31].

The perceived stress that people experience depends not only on the stressors to

which they are subjected, but also on " their appraisals of the situation and

cognitive and emotional responses to it. " [33]

A person's history of both the occurrence of stressors and of the degree of

perceived stress can be evaluated by structured interviews, and this has been

done in a number of studies of CFS risk factors [34-45].

IS THERE EVIDENCE FOR HIGHER OCCURRENCE OF STRESSORS IN CFS PATIENTS PRIOR TO

ONSET THAN IN HEALTHY NORMAL CONTROLS?

YES. The types of stressors found to have higher occurrence in one or more CFS

risk factor studies [34-45] include the following:

Physical: Aerobic exercise (especially of long duration), physical trauma

(especially motor vehicle accidents) and surgery (including anesthesia).

Chemical: Exposure to toxins such as organophosphate pesticides, solvents and

ciguatoxin.

Biological: Infections, immunizations, blood transfusions, insect bites,

allergic reactions, and eating or sleeping less.

Emotional/Psychological:

Stressful life events, including death of a spouse, close family member or close

friend; recent marriage; troubled or failing marriage, separation, or divorce;

serious illness in immediate family; job loss, starting new job, or increased

responsibility at work; and residential move.

Difficulties, including ongoing problems with relationships, persistent work

problems or financial problems, mental or physical violence, overwork, extreme

sustained activity, or " busyness. "

Dilemmas " A dilemma is a situation in which a person is challenged to choose

between two equally undesirable alternatives. " [45] Choosing inaction in response

to a dilemma leads to further negative consequences.

Problems in childhood, including significant depression or anxiety, alcohol or

other drug abuse, and/or physical violence in parents or other close family

members; physical, sexual or verbal abuse, low self-esteem and chronic tension

or fighting in the family.

IS THERE EVIDENCE FOR HIGHER PERCEIVED STRESS IN CFS PATIENTS PRIOR TO ONSET,

COMPARED TO HEALTHY CONTROLS?

YES. Three studies [34, 37, 38] found that CFS patients rated their level of

perceived stress prior to onset higher than did healthy, normal controls for a

similar period of time.

IS IT SURPRISING THAT GLUTATHIONE BECAME DEPLETED IN MANY CFS PATIENTS?

NO. In view of the strong correspondence between the results of the CFS risk

factor studies and the known GSH depletors, it is not surprising. It appears

that the CFS patients who were studied had undergone a variety of factors and

conditions that are known to deplete glutathione, and had also experienced high

levels of perceived stress as a result.

HOW DOES THE NEUROENDOCRINE SYSTEM RESPOND TO STRESS?

This system manifests both specifically- and nonspecifically-induced responses

to stress [32]. The nonspecifically-induced responses address the combined load

of all the various types of stress that are being experienced simultaneously.

The nonspecific responses are mediated by three parts of this sytem: (1) the

hypothalamus-pituitary-adrenal (HPA) axis, which produces cortisol and other

glucocorticoids, (2) the sympathetic-adrenomedullary system, which produces

epinephrine (adrenaline), and (3) the sympathoneural system, which produces

norepinephrine (noradrenaline) [32].

Rapid-onset CFS patients report that they had a normal response to stress prior

to their onset of CFS. Therefore, it can be surmised that if they experienced a

high load of combined long-term stress lasting a few months to several years

prior to their onset, they were subject to high levels of both cortisol and

adrenaline during this extended period of time.

Note that depleted rather than elevated cortisol levels are frequently observed

clinically in CFS patients (Cleare [46]). However, the decrease in cortisol

secretion occurs later in the pathogenesis: " ...the bulk of the data assembled

to date is compatible with the view that the disruption in adrenocortical

function is a late finding, and that elucidating the status of the central

nervous system components which drive the regulation of the HPA axis would be

crucial to a more complete understanding of this final event. " (Demitrack [47])

WHAT ARE THE EFFECTS OF ELEVATED LEVELS OF CORTISOL AND ADRENALINE ON THE IMMUNE

SYSTEM AND ON GLUTATHIONE LEVELS?

Elevation of cortisol is known to suppress the inflammatory response by several

mechanisms, including decreasing the expression of cytokines and cell adhesion

molecules, and decreasing the production of prostaglandins and leukotrienes

[48]. This effect is beneficially used therapeutically in many cases, but it can

also have a down side if an infection is present.

Elevation of cortisol is also known to suppress cell-mediated immunity and to

cause a shift to the Th2 type of immune response. Several mechanisms are

involved, including suppressing the secretion of IL-1 by macrophages, inhibiting

the differentiation of monocytes to macrophages, inhibiting the proliferation of

T lymphocytes, and increasing the production of endonucleases, which increases

the rate of apoptosis of lymphocytes [33,48].

Long-term elevation of adrenaline can be expected to deplete GSH, because

adrenaline decreases the rate of synthesis of glutathione by the liver (Estrela

et al. [18]), increases its rate of export from the liver (Sies and Graf [16];

Haussinger et al. [17]; Estrela et al. [18]), and decreases the rate of

reduction (recycling) of oxidized glutathione (Toleikis and Godin [19]).

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all good,

Duncan

[Guest MBS]

Wow! Thanks for sharing!