Alcohol ADLH2-Deficieny, Esophageal Cancer, and Metabolism

[pharma-sutra]

ADLH2-Deficieny and Squamous Cell Esophageal Cancer

Overview

...it’s basically a genetic inability to properly metabolize alcohol (or ethanol) which, thanks to enzymes in the liver, is normally metabolized first into the toxic chemical acetaldehyde – an animal carcinogen that causes DNA damage and other cancer-promoting effects -- and then into the harmless substance acetate. People with the flushing response have a genetic deficiency in the alcohol-metabolizing enzyme ALDH2, which can lead to an accumulation of the toxic substance acetaldehyde.

The majority of those who experience the glow, which is a result of an inherited deficiency of the enzyme ALDH2 (aldehyde dehydrogenase 2), consider it a cosmetic problem (1). However, recent scientific studies have suggested that ALDH2-deficient individuals who habitually drink alcoholic beverages are at high risk for developing squamous cell esophageal cancer–one of the deadliest cancers in the world (2).

Symptoms include:

...a facial flush and a headache and will feel nauseous at the time they’re drinking. And it’s not just flushing. They’ll also get an increased heart rate. It’s a pretty unpleasant experience.

“Individuals with this particular genetic disposition can’t metabolize it to the acetate,” says Brooks. “So it builds up in their body and causes the vasodilation which causes the flushing response."

underlying cause:

There is a general consensus that a significant percentage of East Asians are subject to a reduction of ALDH activity. For this reason, acetaldehyde accumulates in the body upon alcohol consumption and results in a number of reactions such as histamine release (1).

The reduction of ALDH activity results from a point mutation in the gene that codes for the homotetrameric enzyme ALDH2 (2). ALDH2 is one of two major aldehyde dehydrogenases in normal human livers and is chiefly responsible for metabolizing acetaldehyde in the body (4). East Asian individuals who experience the glow carry an inherited mutated variant of ALDH2 that is enzymatically inactive. The loss of function in the mutant allele (ALDH2*2) is caused by a glutamine to lysine amino acid substitution at position 487 (Table 1) of the wild type allele (ALDH2*1) peptide sequence (4). In the DNA code, the amino acid switch derives from a single base pair difference in exon 12 (selective part of the nucleic acid sequence that is ultimately used as a template for protein/enzyme synthesis) in the ALDH2 gene that is located on chromosome 12 (2).

link to esophageal cancer:

“People with this ALHD2 deficiency have a really high risk of getting esophageal cancer when they drink alcohol,” says Brooks, who wrote about the link between the Asian flush and esophageal cancer in a 2009 paper in PLoS Medicine, a journal published by the Public Library of Science.

the use of famotidine (antacid) in concoction with alcohol consumption alters it's metabolism. Famotidine is often used to alleviate the symptoms accompanied by adlh2-deficiency (ie: facial flush, nausea, bloodshot eyes, etc).

Anecdotal evidence has shown that young people sometimes counter histamine release caused by acetaldehyde accumulation with over-the-counter antiacids such as Zantac and Pepcid Complete (15). An active ingredient and antihistimine in Pepcid Complete, famotidine, can actually reduce the intensity of the facial flushing that many East Asians exhibit upon consuming alcoholic beverages. However, this practice does not facilitate acetaldehyde metabolization and could potentially lead to an even more serious situation as young ALDH2-deficient drinkers feel free to drink more if they don’t have to worry about their faces turning red. As a result, antihistamine use might further elevate the risk for esophageal cancer.

Famotidine increases plasma alcohol concentration in healthy subjects.
http://www.ncbi.nlm.nih.gov/pubmed/8186347

sources:
Esophageal Cancer and the ‘Asian Glow’ - Dartmouth Journal of Science
http://dujs.dartmouth.edu/fall-2009/esophageal-cancer-and-the-%E2%80%98asian-glow%E2%80%99
'Asian flush' red flag for risk of cancer - NBC
http://www.nbcnews.com/health/body-odd/asian-flush-red-flag-risk-cancer-f1C6437432

Now I am definitely for sure adlh2-deficient, and I cannot help but see the correlation between my poor oral-bioavailability with amphetamines and how it's alleviated by famotidine. Here is a link to my other thread in regards to this topic:
http://www.bluelight.org/vb/threads/715442-Poor-Oral-Bioavailability-and-Irritable-Bowel-Syndrome-%28IBS%29

if anyone has any information, please feel free to shed some light.

 

[Captain.Heroin]

Excellent thread, thanks for sharing.

 

[PsychedelicHaze]

So how does pepcid help with the side effects? And does it lessen the acetalhyde?

 

[PsychedelicHaze]

Anyone?

 

[sekio]

Antacids do not actually alter metabolism of ethanol significantly.

In theory more alkaline conditions provide better, more uniform amphetamine absorption.

 

[pharma-sutra]

So how does pepcid help with the side effects? And does it lessen the acetalhyde?

I've updated new info in op that ive retrieved from a more in-depth article. famotidine seems to only mask the physical side-effects. doesn't seem to affect acetaldehyde build-up. also, if someone could ink Brook's study, that'd be great.

@sekio, im assuming you mean adjusting internal alkaline conditions with diet?

 

[PsychedelicHaze]

Ahh thank you guys.

Dang that must mean it's really bad to drink heavily if you're lacking the aldh2 enzyme.

 

[pharma-sutra]

@PsychedelicHaze, i'm assuming you also have the flush reaction? if you don't have nausea, swollen/itchy hands, and the urge to vomit when you consume alcohol then you're probably one of the lucky ones that don't have it too serious. should probably get ethanol patch test done though.

One possible solution is the injection of ALDH2 subcutaneously (underneath the skin) into the bloodstream prior to the consumption of alcohol. This method is derived from diabetics who take insulin injections to regulate the level of glucose in their blood. Now that the glow has been proven to be far more serious than a cosmetic issue, pharmaceutical companies (especially in East Asia) may have sufficient incentive to invent an efficient and cost effective way to produce the enzyme ALDH2 on an industrial scale.
The most promising methods might be the use of transgenic plants to produce mammalian enzymes. Corn crops could be used to produce ALDH2, which would then be extracted using the wet milling process (20). Finally, the ALDH2 could be administered subcutaneously or even orally by means of a pill, powder, or food paste. A rapid-dissolving oral medication would probably be more effective in reducing acetaldehyde levels in the saliva and cancer in the UADT.

This really caught my attention. It could be a gold mine for the big pharmas.