Acetaldehyde and Dimethyl fumarate by #147951 Blog entry

Blog: Minimalist Yeast Abatement Protocol
by #147951

Acetaldehyde and Dimethyl fumarate

Explores the possibility of acetaldehyde and dimethyl fumarate interaction.

Date: 9/25/2012 11:10:56 AM ( 12 y ) ... viewed 5391 times

Given the predilection of acetaldehyde to react with other carbonyls (including itself):

See "Acetaldehyde Aldol Reactions" http://curezone.com/forums/fm.asp?i=1989003

via the nucleophilic (positive-seeking) attack of the acetaldehyde enolate (negative) ion on the slightly positive carbonyl carbon, this opens up an vast array of molecular configurations that may produce beneficial results in a wide variety of conditions. Their ability to interact with yeast-released acetaldehyde because of their available carbonyls may remove free acetaldehyde from the body at the point of contact and be a shared mode of action.

When a carbonyl is adjacent to an ether linkage with an oxygen atom, it is an ester. The simplest ester is methyl formate which is subject to the nucleophilic (Nu) attack reaction common to esters.

Dimethyl fumarate (BG-12) is a methyl unsaturated double ester that has been used to treat psoriasis (since 1959) and recently experimentally for relapse-remitting multiple sclerosis and rheumatoid arthritis with ongoing studies for lupus and cancer.

The instability of acetaldehyde can lead to acetylation of this structure either via its acetyl radical [1] addition to the double bond of the fumarate ester [2] or nucleophilic attack of its enolate ion on either of the carbonyl carbons. Either way acetaldehyde has been denatured from its aldehyde existence by dimethyl fumarate [3].

Given the toxicity profile of free acetaldehyde and its connection to so many disease processes, this would suggest that some of the efficacy of this substance may be a result of this acetaldehyde scavenging ability. Its suspected mode of action is as an immunosuppressive via glutathione (reduced form) depletion [4]. Trying to dampen a hyperactive immune system makes sense if it is really out of control; but if the reason that the immune system is malfunctioning is a result of yeast-released acetaldehyde, then the immunosuppressive aspects of dimethyl fumarate are an unnecessary and undesirable impediment to the body's normal metabolism. Deliberate depletion of glutathione can severely impair the body's ability to cope with reactive oxygen species:

See "Glutathione and Reactive Oxygen Species" http://curezone.com/forums/fm.asp?i=1977665

There are other aspects to the fumarate configuration that suggest it may be active because of its interaction with commensal yeast colonization. It has antifungal properties [5] and is commonly used to kill molds that may cause furniture or shoe leather to deteriorate during storage and transportation. In this regard, so many cases of skin allergy, acute eczema and skin burns resulting from contact with DMF have been reported that it has been banned for usage in this manner by the European Commission [6]. It was also identified as the potent contact sensitizer antagonist in a severe dermatitis epidemic [7].

The connection to acetaldehyde is also found in the usage of fumaric acid in hangover remedies. Although fumaric acid is an intermediate in the citric acid cycle and used as a food additive, therapy with its ester derivatives is associated with side effects [8] including flushing, diarrhea, transaminase elevation, lymphocytopenia, eosinophilia, and disruption of kidney function.

[1] Nakao LS et al., "Metabolism of acetaldehyde to methyl and acetyl radicals: in vitro and in vivo electron paramagnetic resonance spin-trapping studies.", Free Radic Biol Med. 2000 Oct 15;29(8):721-9.
http://www.ncbi.nlm.nih.gov/pubmed/11053773

[2] Chudasama V et al., "Hydroacylation of alpha,beta-unsaturated esters via aerobic C-H activation." Nat Chem. 2010 Jul;2(7):592-6.
http://www.ncbi.nlm.nih.gov/pubmed/20571580

[3] Wiley RH et al.,"γ-Radiation-Induced Addition of Aldehydes to Esters of Maleic, Fumaric, and Acetylenedicarboxylic Acids", J. Org. Chem., 1960, 25 (6), pp 903–904
http://pubs.acs.org/doi/abs/10.1021/jo01076a006

[4] Lehmann JC et al., "Dimethylfumarate induces immunosuppression via glutathione depletion and subsequent induction of heme oxygenase 1.", J Invest Dermatol., 2007 Apr;127(4):835-45. Epub 2007 Jan 18.
http://www.ncbi.nlm.nih.gov/pubmed/17235328

[5] Huhtanen CN et al., "Antifungal Properties of Esters of Alkenoic and Alkynoic Acids", Journal of Food Science, Vol. 49 Iss. 1, p. 281, January 1984.
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2621.1984.tb13726.x/abstract

[6] Chemical Inspection & Regulation Service, "DMF Testing | Directive 2009/251/EC (DMF)", 2009.
http://www.cirs-reach.com/Testing/Dimethyl_Fumarate_DMF_Testing.html

[7] Rantanen T, "The cause of the Chinese sofa/chair dermatitis epidemic is likely to be contact allergy to dimethylfumarate, a novel potent contact sensitizer.", Br J Dermatol., 2008 Jul;159(1):218-21. Epub 2008 Jul 1.
http://www.ncbi.nlm.nih.gov/pubmed/18503603

[8] Nugteren-Huying WM et al., "[Fumaric acid therapy in psoriasis; a double-blind, placebo-controlled study]., Ned Tijdschr Geneeskd 1990 Dec 8;134(49):2387-91.
http://www.ncbi.nlm.nih.gov/pubmed/2263264