Upon consuming alcoholic beverages, hundreds of millions of people of East Asian ethnicity exhibit a facial flushing reaction that is more commonly referred to as the “Asian glow.” 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). In the future, these new findings could ultimately predict an extremely dangerous health problem as levels of alcohol consumption in countries such as China continue to increase (3).

Explaining the ‘Asian Glow’

The two major types of enzymes in the chemical pathway of alcohol metabolism are alcohol dehydrogenases (ADH) and aldehyde dehydrogenases (ALDH).  ADH converts alcohol (ethanol) into acetaldehyde, which ALDH subsequently metabolizes into acetate (Figure 1).

Figure 1: The chemical reaction of alcohol (ethanol) metabolism. Ethanol (CH3CH2OH) is removed from the body through oxidation. Alcohol dehydrogenases (ADH) and aldehyde dehydrogenases (ALDH) catalyze the oxidation of ethanol to acetaldehyde (CH3CHO) and acetaldehyde to acetate (acetic acid or CH3COOH) respectively. The universal electron acceptor, NAD+ (nicotinamide adenine dinucleotide) acts as a coenzyme (i.e. CH3CH2OH + NAD+ → CH3CH=O + NADH + H+).

Figure 1: The chemical reaction of alcohol (ethanol) metabolism. Ethanol (CH3CH2OH) is removed from the body through oxidation. Alcohol dehydrogenases (ADH) and aldehyde dehydrogenases (ALDH) catalyze the oxidation of ethanol to acetaldehyde (CH3CHO) and acetaldehyde to acetate (acetic acid or CH3COOH) respectively. The universal electron acceptor, NAD+ (nicotinamide adenine dinucleotide) acts as a coenzyme (i.e. CH3CH2OH + NAD+ → CH3CH=O + NADH + H+).

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 symptoms of acetaldehyde build-up include facial flushing, nausea, headache, tachycardia, and general physical discomfort (Figure 2).

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).

Figure  2: The facial flushing reaction or ‘Asian glow’ in a 22 year-old male before (left) and after (right) consuming alcohol. This is caused by an accumulation of acetaldehyde, which triggers a histamine release. Other symptoms include nausea, headache, and general physical discomfort.

Figure 2: The facial flushing reaction or ‘Asian glow’ in a 22 year-old male before (left) and after (right) consuming alcohol. This is caused by an accumulation of acetaldehyde, which triggers a histamine release. Other symptoms include nausea, headache, and general physical discomfort.

Among people of East Asian descent, ALDH2*1/ALDH2*2 heterozygotes experience a sharp decrease in ALDH activity in relation to ALDH2*1/ALDH2*1 homozygotes. According to Xiao et al., the mutant variant is only about 8% as effective in metabolizing acetaldehyde as the normal and fully active enzyme (5). However, even with low ALDH2 activity, heterozygotes are still able to consume alcohol. Some individuals are even able to gradually develop a tolerance to acetaldehyde and its symptoms resulting from accumulation. These findings suggest that in heterozygous individuals, ALDH2*1 and ALDH2*2 alleles are both expressed in the phenotype.

Furthermore, ALDH2*2 homozygotes are largely unable to metabolize acetaldehyde. These individuals experience a relatively severe reaction to alcohol and will almost always abstain from drinking alcoholic beverages. As a result, the only carriers of the ALDH2*2 allele that are able to drink on a consistent basis are the ALDH2*1/ALDH2*2 heterozygous individuals (1).

ALDH2-Deficient Individuals and the Risk Factor for Squamous Cell Esophageal Cancer

The most dangerous effect of alcohol-induced acetaldehyde accumulation among ALDH2-deficient individuals (both heterozygous and homozygous carriers of the ALDH2*2 allele) is the elevated risk for developing squamous cell esophageal cancer. Besides being the major metabolite of alcohol, acetaldehyde is also an animal carcinogen and mutagen with recognized cancer-promoting properties (6). ALDH2-deficient drinkers are at risk for developing malignant tumors partially because frequent acetaldehyde exposure at the tissues of the upper aerodigestive tract (UADT), which includes the oral cavity, pharynx, larynx and esophagus, can increase the probability of DNA damage and mutation (Figure 3).

Figure 3: An esophageal squamous cell carcinoma. This ALDH2-deficient individual is a 51 year-old male and has a long history of drinking. The type of cancer exhibited here happens to be one of the deadliest.

Figure 3: An esophageal squamous cell carcinoma. This ALDH2-deficient individual is a 51 year-old male and has a long history of drinking. The type of cancer exhibited here happens to be one of the deadliest.

The tissues of the UADT are most vulnerable to the carcinogenic effects of alcohol because acetaldehyde levels in saliva are 10-20 times higher than in blood (7). One possible explanation for the elevated levels is the presence of microorganisms in the oral cavity that locally produce acetaldehyde (7). In addition, after a moderate dose of alcohol, ALDH2*1/ALDH2*2 heterozygotes were reported to have two to three times the amount of acetaldehyde in their saliva in comparison to their normal ALDH2*1/ALDH2*1 homozygous counterparts (8).

The relatively higher levels of acetaldehyde in the saliva of ALDH2 heterozygotes match with studies demonstrating that ALDH2-deficient drinkers experience acetaldehyde-related DNA damage at a higher frequency than drinkers with fully active ALDH2. The results of a study on Japanese alcoholics suggest that ALDH2-deficient drinkers have higher levels of acetaldehyde-related mutations (Figure 4) in their lymphocytes (a type of white blood cell) than drinkers with wild type ALDH2 (9,10).  These results are in agreement with case-control studies on cancer-free alcoholics that suggest that the relative hazard for developing cancer in the UADT at some point in the future is about 12 times higher for heterozygous drinkers than normal homozygous drinkers (11). Overall, the higher levels of carcinogenic acetaldehyde in the blood and especially the saliva of heterozygotes present a probable mechanism for the causal effect of ALDH2-deficient alcoholism and oncogenesis in the UADT.

Figure 4: Chemical structures of the nucleoside, deoxyguanosine. The upper left molecule is normal, but the remaining three molecules have all undergone acetaldehyde-derived chemical modifications that are represented in red. These modifications can lead to mutations and oncogenesis.

Figure 4: Chemical structures of the nucleoside, deoxyguanosine. The upper left molecule is normal, but the remaining three molecules have all undergone acetaldehyde-derived chemical modifications that are represented in red. These modifications can lead to mutations and oncogenesis.

An Emerging Problem in Global Health

The implications of acetaldehyde-induced esophageal cancer are becoming more troublesome as levels of alcohol consumption in East Asia continue to rise in the 21st century. Although the per capita alcohol consumption in Korea has been declining in recent years, consumption in China has multiplied nine times since 1961 (Figure 5). Similarly, Japan’s alcohol consumption has quadrupled in the past fifty years (1). This is perhaps a function of industrialization, globalization, and rapidly expanding consumer markets in these East Asian nations.

According to researchers, there are at least 540 million ALDH2-deficient individuals in the world — about 8% of the global population (1). However, only a fraction of the ALDH2-deficient population is at risk. This is because ALDH2-deficient individuals who abstain from drinking are not at an elevated risk for esophageal cancer. This includes ALDH2*2/ALDH2*2 homozygotes whose physiological reaction to alcohol is so severe that they are unlikely to drink on a regular basis (3). In addition to these homozygotes, a sizeable fraction of female heterozygotes are also abstainers. In countries like Japan and China, the majority of drinkers are males (12,13). Generally speaking, men consume alcohol in greater quantities and more frequently than women in East Asia and the rest of the world (3). Although there are more than half a billion people with reduced ALDH2 activity, only a fraction of these people — the ones who habitually drink — are at risk.

Still, the number of drinkers among the ALDH2-deficient population is significant and most likely increasing at a rapid rate. In a study by Higuchi et al., archival DNA samples revealed that 3% of Japanese alcoholics were heterozygotes in 1979. The percentage increased to 8% in 1986 and to 13% in 1992 (14). A more recent study found that 26% of males in Tokyo drinking more than 400g (~40 drinks) per week were heterozygotes (6). If the situation in Japan is any indication, than we can infer that the number of Chinese ALDH2-deficient drinkers is rising as well. Most probably, the skyrocketing alcohol consumption in China, the most populated country in the world, will translate into a dramatic increase of people who are ALDH2-deficient, drinking and therefore at high risk for developing deadly esophageal cancer.

Five-year survival rates for esophageal cancer are 15.6% in the United States, 12.3% in Europe, and 31.6% in Japan (1). Japan may have the highest survival rates because hospitals are probably screening for esophageal cancer more frequently and therefore catching it at earlier stages of development. However, if alcohol consumption continues to increase in countries such as China and Japan in the 21st century, then the number of deadly acetaldehyde-related esophageal squamous cell carcinomas could rise to unprecedented numbers.

In addition, the growing population of East Asians in Western societies presents similar problems for the future. Perhaps the subpopulations most at risk are the ALDH2-deficient students in universities all over the United States. These students, who have assimilated into American college culture, may frequently feel social pressure to partake in binge drinking (1). In addition, a heavy drinking lifestyle adopted in college can potentially lead to long-term alcoholism afterwards and further elevate the risk of cancer.

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.

Awareness of Acetaldehyde-Related Cancer

Overall, global awareness of ALDH2 deficiency and its causal relationship with cancer remains relatively low. This is mainly because we have yet to see large numbers of deaths primarily caused by acetaldehyde-induced esophageal cancer. In addition, the research on ALDH2 deficiency is relatively new. In 1981, Harada et al. published the first article that established ALDH deficiency as the direct cause for the glow (16). The first evidence that demonstrated the causal relationship between high levels of acetaldehyde and increased risk factor for esophageal cancer appeared in 1996 (2). Since then, there has been an abundance of documentation in Japan on the potential risks for esophageal cancer that ALDH2-deficient drinkers face. In contrast, only in the past few years has the World Health Organization (WHO) International Agency for Research on Cancer (IARC) started to reassess the carcinogenicity of alcoholic beverages based on the acetaldehyde mechanism. The IARC report of their meeting in February 2007 states: “the substantial mechanistic evidence in humans deficient in aldehyde dehydrogenase indicates that acetaldehyde derived from the metabolism of ethanol in alcoholic beverages contributes to causing malignant oesophageal tumours” (3). The report also states that daily consumption of about four drinks can elevate the risk for UADT cancers by two to three times even for drinkers with fully active ALDH2. For this reason, although moderate alcohol consumption can benefit one’s health, the WHO has listed alcohol consumption as one of the top-10 risks for the worldwide burden of disease (17).

Figure 5: Cross-section illustration of the location and detail of esophageal cancer in the lower esophagus.

Figure 5: Cross-section illustration of the location and detail of esophageal cancer in the lower esophagus.

In spite of this, acetaldehyde-related cancer still remains on the very fringe of public health concerns in Europe and the United States and, by extension, the East Asian populations that live in these Western societies. There have been a few articles in the New York Times and online at PLOS Medicine that have attempted to spread awareness and encourage physicians to communicate the risks to their patients who might be at risk (1). The recent New York Times article “Drinkers’ Red Face May Signal Cancer Risk” has also increased awareness (18). Most likely, articles about acetaldehyde-induced cancer will appear more frequently as research efforts intensify. If the potential dangers surrounding ALDH2-deficiency materialize on a grand scale, then acetaldehyde-induced cancer could become a major health concern among people of East Asian descent.

Preventative Strategies

Currently, the best way to avoid the deaths caused by acetaldehyde-induced esophageal cancer is prevention. According to Brooks et al., 53% of esophageal squamous cell carcinomas could be prevented among Japanese males if moderate and heavy drinking heterozygous individuals became light drinkers (1). For this reason, the most simple and cost effective preventative measure is encouraging ALDH2-deficient individuals to abstain from consuming alcoholic beverages.

To discourage drinking among individuals with reduced ALDH2 activity, general practitioners should inform their East Asian patients of the harmful side effects that the glow can have. Most East Asian adults should know if they are ALDH2-deficient from their previous drinking experiences. If an individual has experienced the glow after one or two drinks, they almost certainly carry an inactive ALDH2*2 allele. Although there are some individuals that stop experiencing the glow after years of drinking, they still carry the ALDH2*2 allele and are at an elevated risk for esophageal cancer (1). East Asian drinkers who are unsure of their genotype can undergo a simple ethanol patch test.

These various methods should give a doctor a clear indication about the patient’s risk factor for developing acetaldehyde-induced cancer. Doctors should also warn their East Asian patients that using tobacco products, which also increase acetaldehyde levels in the saliva and blood, have a synergistic effect when coupled with drinking (19). Lastly, health advisers on university campuses should help ALDH2-deficient college students gain more knowledge about the risks they face if they choose to drink regularly. By spreading awareness, doctors and public health workers could save many lives.

However, while abstinence from alcohol might be the most simple and effective solution, it is not a realistic one. Although some ALDH2-deficient drinkers might adopt healthier lifestyles, there will still be individuals that continue to drink even with the known health risks. For example, Chinese, Japanese, and Korean college students who have adopted the American university drinking culture will most likely continue to binge drink. Similar to many Western societies, drinking has become such a staple in the social environment of cities like Tokyo, Japan that it is almost impossible to imagine that drinking habits will change anytime soon. Over 60 percent of alcoholics in Tokyo are salaried businessmen who frequently drink with clients and colleagues. Among business professionals, drinking is a routine part of their job and a display of company loyalty (12). For this reason, solutions that can lower acetaldehyde in the blood and saliva and reduce the risk of esophageal cancer are needed for ALDH2-deficient individuals who choose to drink on a regular basis.

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.

A more complicated and expensive solution is gene therapy. As previously mentioned, the ALDH2*2 mutant allele is a result of a point mutation. One day, scientists might be able to safely alter the DNA sequence for individual genes. In addition, scientists could possibly introduce fully active normal genes without having to change the native genetic sequence. Both of these methods would increase the amount of ALDH2 being produced in the body. With regards to this subject, Dartmouth College biology professor Eric Lambie comments that, “targeted gene therapy in somatic tissues is still a long ways away, although certainly possible in principle” (21). In reality, gene therapy is far from implementation and is unlikely to develop in the foreseeable future.

In conclusion, now that the link between ALDH2-deficient drinking and esophageal cancer has been elucidated, both scientists and the public will have to determine if this is a health concern that merits the devotion of significant time, energy and resources. There is a distinct possibility that rising levels of alcohol consumption among East Asian populations, in which drinking has not historically been considered a typical cultural practice, could lead to large scale health problems in the 21st century. If the increase in ALDH2-deficient drinking does cause more cases of esophageal cancer, than preventative strategies in the form of reduced alcohol consumption and medications targeting high levels of acetaldehyde will be essential in reducing health care costs and saving lives.

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