By Jackie Man
About 540 million people around the world – 8% of the world population and approximately 36% of East Asians (Japanese, Chinese and Koreans) – have a common characteristic physiological reaction to drinking alcohol in the form of turning red. Though this flushing response may seem like a mere social inconvenience, a far more serious problem lies behind this phenomenon (Brooks et al., 2009).
This flushing response observed in most East Asians in response to alcohol consumption, commonly known as the “Asian flush” or “Asian glow”, is predominantly due to a genetically inherited deficiency in the enzyme aldehyde dehydrogenase 2 (ALDH2), known to interfere with alcohol metabolism (Brooks et al., 2009). Normally, when alcohol is consumed, 90% of it is metabolized and the remaining 10% is excreted unchanged (e.g. through breathing). Of that 90%, 85% is metabolized as it first bypasses the liver, with alcohol dehydrogenase (ADH) catalyzing phase 1 metabolism of alcohol to acetaldehyde (a toxic intermediate highly reactive towards DNA). The remaining 15% is largely metabolized in the stomach, where ADH is also present. After alcohol undergoes phase 1 metabolism, it then undergoes phase 2 metabolism, where a second enzyme, aldehyde dehydrogenase 2 (ALDH2) converts this toxic acetaldehyde into acetic acid. Acetic acid can then be safely metabolized in the body (Zakhari, 2021).
For people who carry wild type ALDH2*1 allele, acetaldehyde can be broken down safely and quickly. However, in the case of people with genetic polymorphism in the gene encoding ALDH2, a point mutation at position 487 from glutamate (Glu) to lysine (Lys) leads to a less efficient mutant ALDH2*2 encoding an inactive protein, resulting in ALDH2 deficiency (J et al., 1994). As a result, enzymatic activity in ALDH2-deficient individuals can be 4% lower than their wild-type counterparts, leading to a buildup of acetaldehyde due to poor alcohol metabolism, which in turn induces an inflammatory response that causes the skin to flush after drinking alcohol (Joshi et al., 2019).
Though turning red is the most obvious result of ALDH2 deficiency, it is also associated with feelings of nausea, headache dizziness, hypotension and heart palpitations, explaining why people with this mutation tend to get sick even with tiny amount of alcohol. These unpleasant effects are results of diverse actions of acetaldehyde in the body, including histamine release (Brooks et al., 2009).
In a study conducted by Matsuda T et al. in Japanese alcoholics, significantly higher amounts of mutagenic acetaldehyde-derived DNA adducts in white blood cells were found in ALDH2-deficient heterozygous individuals compared with active ALDH2 (Matsuda et al., 2006). Additionally, higher levels of white blood cells with chromosomal damage were found in drinkers with ALDH2 heterozygous mutation than drinkers with active ALDH2 (Matsuda et al., 2006). This can be explained as acetaldehyde damages cells through binding to DNA and causing cells to replicate incorrectly, influencing hormone levels which can modify how cells grow and divide. Normally, the cells in our body have a mechanism for repairing alcohol induced DNA damage by breaking down the alcohol normally produced in the body. However in the case of drinkers who are ALDH2-deficient, this normal DNA repair mechanism may be overwhelmed, resulting in acetaldehyde accumulation. When this accumulation reaches a toxic level, it will then lead to tissue damage and increasing absorption of other carcinogens which are commonly associated with increased risks of esophageal cancer, heart attacks and osteoporosis, as compared to the general population (Brooks et al., 2009).
In fact, ALDH2-deficient drinkers are at a higher risk of developing malignant tumors partially because the upper aerodigestive tract (UADT), which includes the oral cavity, pharynx, larynx and esophagus is frequently exposed to acetaldehyde. This increases the probability of DNA damage and mutation. As acetaldehyde levels in saliva in UADT are 10-20 times higher than in blood, tissues in UADT are most vulnerable to carcinogenic effects of alcohol in presence of microorganisms in the oral cavity that locally produce acetaldehyde, leading to increased risk of esophageal cancer (Mizumoto et al., 2017).
Interestingly, studies have also shown a potential link between ALDH2*2 mutation and Alzheimer’s Disease (AD). For instance, an in vivo model of ALDH2*2 mutant mice showed that a daily exposure to ethanol for 11 weeks resulted in increased aldehyde levels in the brains, following mitochondrial dysfunction and increased oxidative stress as compared to the WT (Joshi et al., 2019). Accumulation of beta-amyloid protein fragments and activated tau protein were also observed in much higher levels in the mutant mice compared to the WT. Both of these changes are molecular signatures for Alzheimer’s disease (Joshi et al., 2019). These findings indicate ALDH2’s potential uncharacterized role in the development and progression of Alzheimer’s disease.
Given the strong association between ALDH2 polymorphism and certain alcohol-related cancers, more attention should be brought to this rare disease, especially in East Asian countries where nearly half of the population is ALDH2-deficient. Although more research needs to be done investigating the link between ALDH2-deficiency and increased risks of alcohol-associated cancers, preventive strategies in the form of reduced alcohol consumption and medications targeting high levels of acetaldehyde will be essential in the future of healthcare regarding “Asian Flush”.
- Brooks, P., Enoch, M., Goldman, D., Li, T. and Yokoyama, A., 2009. The Alcohol Flushing Response: An Unrecognized Risk Factor for Esophageal Cancer from Alcohol Consumption. [online] Available at: <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2659709/> [Accessed 9 March 2021].
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- Joshi, A., Van Wassenhove, L., Logas, K., Minhas, P., Andreasson, K., Weinberg, K., Chen, C. and Mochly-Rosen, D., 2019. Aldehyde dehydrogenase 2 activity and aldehydic load contribute to neuroinflammation and Alzheimer’s disease related pathology. [online] Available at: <https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-019-0839-7> [Accessed 9 March 2021].
- Matsuda, T., Yabushita, H., Kanaly, R., Shibutani, S. and Yokoyama, A., 2006. Increased DNA Damage in ALDH2-Deficient Alcoholics. [online] Available at: <https://pubmed.ncbi.nlm.nih.gov/17040107/> [Accessed 9 March 2021].
- Mizumoto, A., Ohashi, S., Hirohashi, K., Amanuma, Y., Matsuda, T. and Muto, M., 2017. Molecular Mechanisms of Acetaldehyde-Mediated Carcinogenesis in Squamous Epithelium. [online] Available at: <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618592/> [Accessed 9 March 2021].
- Zakhari, S., 2021. NIAAA Publications. [online] Pubs.niaaa.nih.gov. Available at: <https://pubs.niaaa.nih.gov/publications/arh294/245-255.htm> [Accessed 9 March 2021].