PLoS Medicine | www.plosmedicine.org0258March 2009 | Volume 6 | Issue 3 | e1000050
Research in Translation
The Alcohol Flushing Response:An Unrecognized Risk Factor for EsophagealCancer from Alcohol Consumption
Philip J. Brooks*, Mary-Anne Enoch, David Goldman, Ting-Kai Li, Akira Yokoyama*
pproximately 36% of East Asians (Japanese, Chinese, andKoreans) show a characteristicphysiological response to drinkingalcohol that includes facial flushing(see Figure 1), nausea, and tachycardia . This so-called alcohol flushingresponse (also known as “Asian flush”or “Asian glow”) is predominantly due to an inherited deficiency in theenzyme aldehyde dehydrogenase 2(ALDH2) . Although cliniciansand the East Asian publicgenerally know about the alcohol flushingresponse (e.g., http://www.echeng.com/asianblush/), few are awareof the accumulating evidence that ALDH2-deficient individuals are at much higher risk of esophageal cancer(specifically squamous cell carcinoma)from alcohol consumption thanindividuals with fully active ALDH2.This is particularly unfortunate asesophageal cancer is one of thedeadliest cancers worldwide , withfive-year survival rates of 15.6% in theUnited States, 12.3% in Europe, and31.6% in Japan .Our goal in writing this article isto inform doctors firstly that their ALDH2-deficient patients have anincreased risk for esophageal cancerif they drink moderate amounts of alcohol, and secondly that the alcoholflushing response is a biomarkerfor ALDH2 deficiency. Because of the intensity of the symptoms, most people who have the alcohol flushingresponse are aware of it. Thereforeclinicians can determine ALDH2deficiency simply by asking about previous episodes of alcohol-inducedflushing. As a result, ALDH2-deficient patients can then be counseled toreduce alcohol consumption, andhigh-risk patients can be assessed forendoscopic cancer screening. Based onthe sizes of the Japanese, Chinese, andKorean populations and the expectedfrequency of ALDH2-deficient individuals in each , we estimate that there are at least 540 million ALDH2-deficient individuals in the world,representing approximately 8% of thepopulation. In a population of this size,even a small reduction in the incidenceof esophageal cancer could result ina substantial reduction in esophagealcancer deaths worldwide.
A Primer on the Genetics of Alcohol Metabolism
Ethanol is first metabolized primarily by alcohol dehydrogenase (ADH) intoacetaldehyde (Figure 2), a mutagenand animal carcinogen that causesDNA damage and has other cancer-promoting effects [5–7]. Acetaldehydeis subsequently metabolized to acetate,mainly by the enzyme ALDH2 . InEast Asian populations there are twomain variants of
, resultingfrom the replacement of glutamate(Glu) at position 487 with lysine (Lys). The Glu allele (also designated
) encodes a protein withnormal catalytic activity, whereasthe Lys allele (
) encodesan inactive protein. As a result, Lys/Lys homozygotes have no detectable
The authors received no specific fundingfor this article.
The authors have declaredthat no competing interests exist.
BrooksPJ, Enoch M-A, Goldman D, Li T-K,Yokoyama A (2009)The alcohol flushing response:An unrecognized risk factor for esophageal cancerfrom alcohol consumption.PLoS Med 6(3): e1000050.doi:10.1371/journal.pmed.1000050 This is an open-access article distributed under theterms of the Creative Commons Public Domaindeclaration, which stipulates that, once placed in thepublic domain, this work may be freely reproduced,distributed, transmitted, modified, built upon, orotherwise used by anyone for any lawful purpose.
ADH, alcohol dehydrogenase;ALDH2, aldehyde dehydrogenase 2; Glu, glutamate;Lys, lysine; OR, odds ratio; UADT, upper aerodigestivetractPhilip J. Brooks, Mary-Anne Enoch, and DavidGoldman are in the Laboratory of Neurogenetics,National Institute on Alcohol Abuse and Alcoholism,National Institutes of Health, Rockville, Maryland,United States of America. Ting-Kai Li is the formerDirector of the National Institute on Alcohol Abuseand Alcoholism, National Institutes of Health. He isnow a Professor at the Duke–National University of Singapore Graduate Medical School, Durham, NorthCarolina, United States of America. Akira Yokoyamais Director of Clinical Research Unit, National HospitalOrganization Kurihama Alcoholism Center, Nobi,Yokosuka, Kanagawa, Japan. Philip J. Brooks andAkira Yokoyama were participants in the 2007International Agency for Research on Cancer WorkingGroup on alcoholic beverage consumption.* To whom correspondence should be addressed.E-mail: email@example.com; firstname.lastname@example.org
Not commissioned; externally peerreviewed
Lys487 allele contributes toboth the alcohol flushing responseand an elevated risk of squamouscell esophageal cancer from alcoholconsumption.
useful clinically, as it allows doctors toidentify their ALDH2-deficient patientsin a simple, cost-effective, and non-invasive manner.
deficient patients to limit alcoholconsumption and thereby reduce therisk of developing esophageal cancer.
million ALDH2-deficient individuals inthe world, many of whom now live inWestern societies, even a small percentreduction in esophageal cancers dueto a reduction in alcohol drinkingwould translate into a substantialnumber of lives saved.
Research in Translation discusses health interventionsin the context of translation from basic to clinicalresearch, or from clinical evidence to practice.