Source: blogs.plos.org
Author: Catherine Chang et al.

Turning red after consuming alcohol may seem like a mere social inconvenience. Yet, behind this red complexion lies a far more serious problem. ALDH2 deficiency, more commonly known as Alcohol Flushing Syndrome or Asian Glow, is a genetic condition that interferes with the metabolism of alcohol. As a result, people with ALDH2 deficiency have increased risks of developing esophageal and head and neck cancers . Globally, this deficiency affects 540 million people — 8% of the world population. In East Asia (which includes Japan, China, and Korea), this is a much bigger problem, where 36% of the population is affected [1]. In our home, Taiwan, approximately 47% of the population carries this genetic mutation — the highest percentage in the world [2]!

Normally, ethanol is first converted to acetaldehyde (a toxic intermediate) by the enzyme alcohol dehydrogenase (ADH). A second enzyme, aldehyde dehydrogenase 2 (ALDH2), then converts toxic acetaldehyde into acetate, a compound which can be safely metabolized in the body. For people who carry wild type ALDH2*1, acetaldehyde can be broken down quickly. People with ALDH2 deficiency, however, have a point mutation which leads to the less efficient mutant ALDH2*2 [3], [4]. Enzymatic activity in ALDH2-deficient individuals can be as low as 4% compared to wild type [4], [5], [6], [7]. As a result, acetaldehyde accumulates and induces an inflammatory response that causes the skin to flush after drinking alcohol [8]. Turning red is the most obvious result of ALDH2 deficiency, but symptoms also include headaches, dizziness, hypotension, and heart palpitations [5], [9].

Acetaldehyde accumulates in ALDH2-deficient individuals. Ethanol is first converted to a toxic intermediate, acetaldehyde, by ADH, then converted to acetate by wild type ALDH2*1. The mutant form, ALDH2*2, cannot fully convert acetaldehyde into acetate, and toxic acetaldehyde accumulates as a result.

For people who are ALDH2-deficient and drink, acetaldehyde can accumulate to toxic levels. The International Agency for Research on Cancer classifies acetaldehyde associated with alcohol consumption as a Group 1 carcinogen [10]. Acetaldehyde levels over 50 μM are considered toxic and cause mutations in DNA, and studies show that the strongest effects are seen in the mouth [11], [12]. After consuming roughly 2 to 3 servings of alcohol (0.5-0.6 g alcohol/kg body weight), salivary acetaldehyde levels in ALDH2-deficient individuals reached over 100 μM, compared to normal levels of <20 μM without drinking [13], [14], [15], [16]. Because of the increased salivary acetaldehyde, people with ALDH2 deficiency are 2 to 8 times more likely to develop head and neck cancers (including oral cancer, pharyngeal cancer, laryngeal cancer, etc.), and 2 to 12 times more likely to develop esophageal cancer compared to people with normal ALDH2*1 [17-25].

Our ALDH2*1 probiotic candy significantly reduces acetaldehyde levels in simulated oral conditions. (A) The conversion of acetaldehyde to acetate by ALDH2 uses NAD+ and produces NADH. (B) Experimental setup. The candies were dissolved, the probiotic (Nissle) was lysed to release ALDH2 enzymes, and the supernatant was placed into artificial saliva. NADH concentration was measured by taking absorbance readings at 340 nm. (C) Enzymatic activity of ALDH2*1 and ALDH2*2 from the probiotic candies. A negative control of candy without Nissle was also included (gray). Under these conditions, the ALDH2*1 candies metabolized significantly more acetaldehyde compared to both the ALDH2*2 candies and the negative control. Error bars represent standard error.

To directly address the increased esophageal and head and neck cancer risks, we developed a probiotic (E. coli Nissle 1917) candy carrying recombinant human ALDH2*1 to maintain normal acetaldehyde levels in the mouths of ALDH2-deficient individuals. We tested the candy’s ability to break down acetaldehyde by measuring NADH, a byproduct of acetaldehyde metabolism. In simulated oral conditions, we observed a significant decrease in acetaldehyde levels when we added the contents of our ALDH2*1 candy (compared to the mutant ALDH2*2 or control candy). Through mathematical modeling, we also determined the exact amount of recombinant ALDH2*1 needed in each piece of candy. Our modeling shows that if a consumer eats our candy while drinking, the released ALDH2*1 will be able to combat the high salivary acetaldehyde levels and match the normally low levels found in wild type individuals.

 

Our final product, an ALDH2*1 probiotic candy!

Nearly half of Taiwan’s population is ALDH2 deficient. To combat the increased cancer risks associated with this deficiency, we developed and tested a method to regulate acetaldehyde levels in ALDH2-deficient individuals.

The TAS_Taipei iGEM Team have produced a full research article detailing their project. You can access that article here.

Note:Please note that the team’s full research article has not been peer-reviewed.

Authors: Catherine Chang, Tim Ho, Iris Huang, Justin Wu

References:
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