Re: Detoxifying acetaldahyde

The pulsed low-dosage acetaldehyde exposure associated with yeast fermentation of carbohydrates doesn't cause a sudden shutdown of the body's sulfur metabolism, of course. Once an acetaldehyde molecule reacts with something (almost anything, it seems), then its ability to damage something else is limited. However, the continuous exposure to newly generated acetaldehyde with spikes at every mealtime (or Sugar binge) produces an incrementally cumulative effect in sensitive areas. Depending upon what has been targeted, there can be a "ripple effect" of downstream consequences. If acetaldehyde is disabling thyroid TSH receptors, for example, then every cell in the body that is dependent upon competent thyroid function can be impaired:

See "Thyroid + Acetaldehyde" //www.curezone.org/forums/fm.asp?i=1955669

When some temporally destabilizing event such as a course of Antibiotics or diversion of immune system resources into a bout with the flu occurs, for example, then the background yeast load may increase dramatically as a consequence. The more yeast cells there are, the more acetaldehyde there is that the body has to cope with on a daily basis.

This creates a measurable erosion in biomarkers such as the extracellular plasma cysteine/cystine (Cys/CySS) redox pool:

See "Cys/CySS + ROS" //www.curezone.org/forums/fm.asp?i=1975696

The status of this redox pool is closely coupled to the competence of the major intracellular antioxidant redox system, glutathione/glutathione disulfide (GSH/GSSG). Glutathione is a tripeptide made up of the three amino acids glutamate, cysteine, and glycine:



Of the three constituents, dietary cysteine, that contributes the critical sulfhydryl group, is the most likely rate-limiting step for the synthesis of glutathione within the cell. Glutathione not only participates directly in the neutralization of reactive oxygen species (ROS), it also assists other antioxidants such as vitamins C and E by returning them to their reduced (active) forms.

Although acetaldehyde doesn't appear to react directly with glutathione [1], it does react with its precursor amino acid cysteine:

See "Cysteine + Acetaldehyde" //www.curezone.org/forums/fm.asp?i=1973900

and a glutathione metabolite cysteinylglycine to form thiazolidinecarboxylic acid derivatives. It can also interfere with the backup supply pathway from dietary methionine to cysteine:

See "Methionine + Acetaldehyde" //www.curezone.org/forums/fm.asp?i=1977201

This means that acetaldehyde released by yeast has the potential for clobbering both of the vital sulfur-based redox pools: Cys/CySS and GSH/GSSG.

Although there is some control over cellular ROS exerted by redox pools from outside the cell [2], in order to establish its own redox pools inside a cell, the cell must first transport the necessary molecules through its membrane and into the intracellular milieu. Since the systemic availability of oral glutathione (GSH) is negligible [3], the vast majority of it must be manufactured intracellularly and since cysteine is the limiting resource in this regard, cellular uptake of plasma cysteine is essential. Cystine is a ubiquitous disulfide of back-to-back cysteine molecules generated from cysteine by an oxidase on extracellular surfaces [4].

The oxidative stress-inducible cystine/glutamate antiporter system transports one molecule of cystine, the oxidized form of cysteine, through the cellular membrance in exchange for one glutamate molecule which is released into the extracellular space [5]. The cystine molecule inside the cell can then supply two cysteine molecules for glutathione biosynthesis. When cystine uptake by the cystine/glutamate antiporter system is inhibited [6] or impaired, creating a void in the antioxidant defenses of a cell, this leads ultimately to an accumulation of toxic ROS in the cell and eventual cellular death [7].

Since the toxic levels of ROS lipids in a cell associated with impaired cystine availability will spawn malondialdehyde:

See "Malondialdehyde" //www.curezone.org/forums/fm.asp?i=1976523

this implies that not only are acetaldehyde and malondialdehyde both tiny, look-alike deadly aldehydes [8]:



but also that there is a chain of causation from yeast-released acetaldehyde through disruption of sulfur redox pools to the accumulation of malondialdehyde in cells, a sign of oxidative stress that usually heralds the death knell of the cell.

Whether directly or indirectly, not only does acetaldehyde accelerate the rate of cell death [9] but it retards the rate of replacement [10] leading to chronic wasting away of body tissue, all the while hiding under the cover of increased oxidative stressors. Many diseases of unknown origin are associated with oxidative stress biomarkers [11,12]. In fact it is a rare disease state indeed that isn't associated with abnormalities in the redox pools. But instead of being a consequence of whatever abnormality is occurring, perhaps this redox pool insufficiency is the driving force. Even in the absence of apparent illness, the rapidity of the aging process is linked to redox pool competence [13].

Which of the acetaldehyde pathways explored to date is responsible for the downward spiral into disease? Given its reactivity, any and all of the possibilities explored thus far may play a role. However, the impairment of the redox status of every cell in the body is going to be at least a major, if not the most significant, factor in conditions of progressively chronic failure.

Given the criticality of dietary sulfur metabolism in this regard and given the affinity of acetaldehyde for binding to sulfur-bearing structures, it should no longer be so surprising that Wondro produced beneficial results in so many apparently unrelated diseases. By sacrificing its metabolically useless disulfide bonds to irreversible binding with acetaldehyde, it allowed the function of critically essential sulfur pathways to return to normal, thereby reducing the overall load of oxidative stress on each and every cell, and permitting the body to heal itself.

[1] Kera Y et al., "Conjugation of acetaldehyde with cysteinylglycine, the first metabolite in glutathione breakdown by gamma-glutamyltranspeptidase.", Agents Actions. 1985 Oct;17(1):48-52.
http://www.ncbi.nlm.nih.gov/pubmed/2867670

[2] Imhoff Br et al., "Extracellular redox status regulates Nrf2 activation through mitochondrial reactive oxygen species." Biochem J. 2009 Dec 10;424(3):491-500
http://www.ncbi.nlm.nih.gov/pubmed/19778293

[3] Witschi A et al., "The systemic availability of oral glutathione.", Eur J Clin Pharmacol. 1992;43(6):667-9.
http://www.ncbi.nlm.nih.gov/pubmed/1362956

[4] Jones DP et al., "Cysteine/cystine couple is a newly recognized node in the circuitry for biologic redox signaling and control.", FASEB J. 2004 Aug;18(11):1246-8.
http://www.ncbi.nlm.nih.gov/pubmed/15180957

[5] Conrad M et al., "The oxidative stress-inducible cystine/glutamate antiporter, system x (c) (-) : cystine supplier and beyond.", Amino Acids. 2012 Jan;42(1):231-46.
http://www.ncbi.nlm.nih.gov/pubmed/21409388

[6] Dixon SJ et al., "Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death.", Cell, Vol 149(5), 1060-1072, 25 May 2012
http://www.ncbi.nlm.nih.gov/pubmed/22632970

[7] Banjac A et al., "The cystine/cysteine cycle: a redox cycle regulating susceptibility versus resistance to cell death.", Oncogene. 2008 Mar 6;27(11):1618-28. Epub 2007 Sep 10.
http://www.ncbi.nlm.nih.gov/pubmed/17828297

[8] Wyatt TA et al., "Malondialdehyde-acetaldehyde adducts decrease bronchial epithelial wound repair.", Alcohol. 2005 May;36(1):31-40.
http://www.ncbi.nlm.nih.gov/pubmed/16257351

[9] Menegola E et al., "Acetaldehyde in vitro exposure and apoptosis: a possible mechanism of teratogenesis." Alcohol. 2001 Jan;23(1):35-9.
http://www.ncbi.nlm.nih.gov/pubmed/11282450

[10] Zimmerman BT et al., "Mechanisms of acetaldehyde-mediated growth inhibition: delayed cell cycle progression and induction of apoptosis.", Alcohol Clin Exp Res. 1995 Apr;19(2):434-40.
http://www.ncbi.nlm.nih.gov/pubmed/7625579

[11] Perez YG et al., "Malondialdehyde and sulfhydryl groups as biomarkers of oxidative stress in patients with systemic lupus erythematosus.", 2012 Aug;52(4):658-660.
http://www.ncbi.nlm.nih.gov/pubmed/22885431

[12] Pampliega O et al.,"Increased expression of cystine/glutamate antiporter in multiple sclerosis.", J Neuroinflammation. 2011 Jun 3;8:63.
http://www.ncbi.nlm.nih.gov/pubmed/21639880

[13] Droge W, "Aging-related changes in the thiol/disulfide redox state: implications for the use of thiol antioxidants.", Exp Gerontol. 2002 Dec;37(12):1333-45.
http://www.ncbi.nlm.nih.gov/pubmed/12559403
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