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Aldehyde Dehydrogenase Deficiency as Cause of Facial Flushing Reaction to Alcohol in Japanese

Aldehyde Dehydrogenase Deficiency as Cause of Facial Flushing Reaction to Alcohol in Japanese SEMINAL ARTICLES low, even immediately after alcohol consumption when acetaldehyde is being generated rapidly in the liver. Multiple aldehyde dehydrogenase enzymes exist and their structures are determined by different genes; however, this commentary examines o n l y t h e e n z y m e ( d e s i g n a t e d a s ALDH2) that is imported into the mitochondrion, the cell’s energy­ producing structure. The seminal ar­ t i c l e b y H a r a d a a n d c o l l e a g u e s , which actually is a detailed letter to the editor of the journal Lancet, first related the discovery of the effect of a genetic variant of this enzyme, which occurs very abundantly in Oriental populations (East Asians). ALDH2 is key in the metabolism of acetaldehyde produced after alco­ hol consumption. In 1948 Hald and J a c o b s e n i n t r o d u c e d d i s u l f i r a m (Antabuse ), an inhibitor of alde­ hyde dehydrogenase, for the clinical treatment of alcoholics. Disulfiram­ treated subjects who consume alco­ hol accumulate relatively high levels of acetaldehyde. These high acet­ aldehyde levels lead to an aversive response known as the flushing reac­ tion. In addition to a facial flush, the flushing reaction also may include an elevated heart rate (i.e., tachycar­ dia), headache, heart palpitations, shortness of breath (i.e., dyspnea), hyperventilation, low blood pressure (i.e., hypotension), vertigo, nausea, and vomiting. Certain other drugs that also inhibit aldehyde dehydroge­ nase, such as metronidazole, were found to cause flushing in associa­ tion with alcohol intake. This flush­ ing reaction also occurs naturally in some people. However, the blockade of aldehyde dehydrogenase actually Harada, S.; Agarwal, D.P.; and Goedde, H.W. Aldehyde dehydrogenase deficiency as cause of facial flushing reaction to was used to treat alcoholism long be­ alcohol in Japanese. Lancet ii(8253):982, 1981. fore the mechanism that causes natu­ rally occurring alcohol­induced flushing was discovered. ALDEHYDE DEHYDROGENASE DEFICIENCY Harada and colleagues directly related naturally occurring AS CAUSE OF FACIAL FLUSHING aldehyde dehydrogenase blockade to elevated acetaldehyde lev­ els and flushing. Wolff (1972) and others (Zeiner et al. 1979) REACTION TO ALCOHOL IN JAPANESE had observed that unmedicated Japanese and people from neigh­ boring regions of Asia often showed the same flushing response Commentary by David Goldman, M.D. after intake of relatively small quantities of alcohol. In 1981 Harada and colleagues Agarwal and Goedde showed that some KEY WORDS: aldehyde dehydrogenase; alcohol flush reaction; people were naturally deficient in the aldehyde dehydrogenase Asian; metabolism; acetaldehyde; genetics and heredity; enzyme (Agarwal et al. 1981). By using a technique (i.e., protein AOD dependence electrophoresis) that separates the enzyme in an electric field, ldehyde dehydrogenase is an enzyme responsible for the followed by a stain for the enzyme, they found that acetaldehyde A breakdown of acetaldehyde, a toxic intermediate produced dehydrogenase was structurally different in people in whom the directly from the metabolism of alcohol. Aldehyde dehydrogenase aldehyde dehydrogenase activity was deficient. One year later these researchers published their seminal letter to the editor of is extraordinarily efficient in keeping acetaldehyde levels very 48 ALCOHOL HEALTH & RESEARCH WORLD SEMINAL ARTICLES Lancet, relating findings that closed the link between the alde­ Much of the current excitement in alcohol research revolves hyde dehydrogenase enzyme deficiency and alcohol­induced around identifying genetic factors that, like ALDH2 , act to in­ flushing. People with the deficient aldehyde dehydrogenase were fluence a person’s vulnerability to alcohol but that act at the lev­ clearly shown to be those with high acetaldehyde levels after al­ el of the brain. Such factors may lead a person to seek alcohol cohol consumption. more avidly and respond to it with greater or lessor sensitivity. A cascade of research was triggered by the observations Intensive family studies, such as the National Institute on Harada and colleagues reported in this letter. The precise Al c o h o l A b u s e a n d Al co h o li sm’ s C o l labo r a ti v e St u d y o n d e m o n s t r a t i o n t h a t t h e f u n c t i o n a l d i f f e r e n c e i n a l c o h o l Genetics of Alcoholism (COGA), are underway to identify such metabolism in people with East Asian ancestry was attributable factors. Once the genes are identified, gene­environment and to a structural difference in ALDH2 led to studies of the enzyme gene­gene interaction studies will be required to better under­ protein and of the gene that determines this enzyme. It could be stand the forces that combine in the development of vulnerability said that, for alcoholism, the molecule of the 1980’s was alde­ for alcoholism. The epidemiological studies on ALDH2 show hyde dehydrogenase. Two years after this letter appeared, that such genetic factors act probabilistically rather than deter­ Yoshida and colleagues (1984) showed that the cause of ALDH2 ministically to influence alcoholism vulnerability. In other inactivation in East Asian subjects was a substitution of a single words, people with a genetic vulnerability factor may have a amino acid (i.e., lysine substituted for glutamate in position 487 higher probability of becoming alcoholics, but they are not pre­ of the protein chain). This amino acid substitution was itself destined to developing the disease. found to result from a single DNA base substitution among the What are the factors that influence some individuals to become t h o u s a n d s o f D N A b a s e s t h a t m a k e u p t h e A L D H 2 g e n e . alcoholics, even though they have aldehyde dehydrogenase defi­ Structurally, the aldehyde dehydrogenase enzyme is composed ciency? Studies of alcoholics who carry the protective aldehyde of four usually identical subunits (i.e., it is a tetramer). The dehydrogenase variant may reveal other genetic and nongenetic tetramer was found to be inactivated if even one of its four sub­ factors that lead to alcoholism or that are protective for alco­ units had the glutamate 487 substitution. It is for this reason that holism. Examples of gene­gene and gene­environmental influ­ the inactive variant of the gene, designated ALDH2 , follows a ences involving aldehyde dehydrogenase include the finding that dominant pattern of inheritance. For example, if the version of variations in alcohol dehydrogenase play an interacting role in al­ ALDH2 inherited from either one of an individual’s parents is coholism vulnerability (Thomasson et al. 1991) and the discovery ALDH2 , there is nearly a complete loss of aldehyde dehydroge­ that vulnerability to alcoholism is increased in East Asians who nase enzyme activity. Geneg ­ eography studies revealed that aldehyde dehydrogenase have immigrated to North America. ■ deficiency was highest in people from East Asia and absent or nearly absent in whites and blacks. DNAb ­ ased tests showed that D A V I D G O L D M A N , M.D. , i s d i r e c t o r o f t h e L a b o r a t o r y o f the DNA substitution responsible for the deficiency was the same Neurogenetics in the Division of Intramural Clinical and across populations and also within populations in which the defi­ Biological Research at the National Institute on Alcohol Abuse ciency is abundant. Epidemiological studies of populations with a and Alcoholism, Bethesda, Maryland. high prevalence of ALDH2 revealed that aldehyde dehydrogenase deficiency dramatically lowers vulnerability to alcoholism. In do­ ing so, ALDH2 deficiency interacts with other factors, including a REFERENCES common, superactive genetic variant of alcohol dehydrogenase AGARWAL, D.P.; HARADA, S.; AND GOEDDE, H.W. Racial differences in biological (ADH2 ) which increases the rate that acetaldehyde is produced. sensitivity to ethanol: The role of alcohol dehydrogenase and aldehyde dehydroge­ Thus, a single DNA nucleotide difference, present in hundreds of nase isozymes. Alcoholism: Clinical and Experimental Research 5:12–16, 1981. millions of people, profoundly influences their experiences with alcohol and vulnerability to alcoholism. HALD, J., AND JACOBSEN, E. The sensitizing effect of tetraethylthiuram disulphide A mark of good scientific paradigms is their propensity for (Antabuse) to ethyl alcohol. Lancet ii:1001–1004, 1948. shaping the future by posing answerable questions that open new intellectual vistas. For aldehyde dehydrogenase, many of the HARADA, S.; AGARWAL, D.P.; AND GOEDDE, H.W. Aldehyde dehydrogenase defi­ most interesting and humanistically most significant questions ci en c y a s ca use of fa c ia l flu s hi ng reac tio n to al c oho l in J ap an e se. Lancet remain unanswered. For example, what are the additional risks ii(8253):982, 1981. besides flushing for people with aldehyde dehydrogenase defi­ ciency who consume alcohol? This question is being intensively THOMASSON, H.R.; EDENBERG, H.J.; CRABB, D.; MAI, X.­L.; JEROME, R.E.; LI, explored in several ways, including comparing alcoholics with T.­K.; WANG, S.­P.; LIN, Y.­T.; LU, R.­B.; AND YIN, S.­J. Alcohol and aldehyde de­ and without liver disease. hydrogenase genotypes and alcoholism in Chinese men. American Journal of Researchers are only beginning to ask other important ques­ Human Genetics 48:677–681, 1991. tions. For example, why do East Asians so frequently have alde­ WOLFF, P. Ethnic differences in alcohol sensitivity. Science 125:449–451, 1972. hyde dehydrogenase deficiency—by chance or necessity (i.e., was there some biological [selective] advantage in ancient times and is YOSHIDA, A.; HUANG, I.Y.; AND IWAKA, M. Molecular abnormality of an inactive there any current advantage to possessing the ALDH2 gene)? Do aldehyde dehydrogenase variant commonly found in Orientals. Proceedings of the people who abstain from alcohol use suffer any negative conse­ National Academy of Sciences, USA 81:259–261, 1984. quences of aldehyde dehydrogenase deficiency? ZIENER, A.R.; PAREDES, A.; AND CHRISTENSEN, C.H. The role of acetaldehyde in A chemical compound formed as an intermediate step between the initial form mediating reactivity to an acute dose of alcohol among different racial groups. Alcoholism: Clinical and Experimental Research 3:11–18, 1979. (i.e., alcohol) and the final product (i.e., acetate). VOL. 19, NO. 1, 1995 49 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Alcohol Health and Research World Pubmed Central

Aldehyde Dehydrogenase Deficiency as Cause of Facial Flushing Reaction to Alcohol in Japanese

Goldman, David
Alcohol Health and Research World , Volume 19 (1) – Mar 1, 167
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Abstract

SEMINAL ARTICLES low, even immediately after alcohol consumption when acetaldehyde is being generated rapidly in the liver. Multiple aldehyde dehydrogenase enzymes exist and their structures are determined by different genes; however, this commentary examines o n l y t h e e n z y m e ( d e s i g n a t e d a s ALDH2) that is imported into the mitochondrion, the cell’s energy­ producing structure. The seminal ar­ t i c l e b y H a r a d a a n d c o l l e a g u e s , which actually is a detailed letter to the editor of the journal Lancet, first related the discovery of the effect of a genetic variant of this enzyme, which occurs very abundantly in Oriental populations (East Asians). ALDH2 is key in the metabolism of acetaldehyde produced after alco­ hol consumption. In 1948 Hald and J a c o b s e n i n t r o d u c e d d i s u l f i r a m (Antabuse ), an inhibitor of alde­ hyde dehydrogenase, for the clinical treatment of alcoholics. Disulfiram­ treated subjects who consume alco­ hol accumulate relatively high levels of acetaldehyde. These high acet­ aldehyde levels lead to an aversive response known as the flushing reac­ tion. In addition to a facial flush, the flushing reaction also may include an elevated heart rate (i.e., tachycar­ dia), headache, heart palpitations, shortness of breath (i.e., dyspnea), hyperventilation, low blood pressure (i.e., hypotension), vertigo, nausea, and vomiting. Certain other drugs that also inhibit aldehyde dehydroge­ nase, such as metronidazole, were found to cause flushing in associa­ tion with alcohol intake. This flush­ ing reaction also occurs naturally in some people. However, the blockade of aldehyde dehydrogenase actually Harada, S.; Agarwal, D.P.; and Goedde, H.W. Aldehyde dehydrogenase deficiency as cause of facial flushing reaction to was used to treat alcoholism long be­ alcohol in Japanese. Lancet ii(8253):982, 1981. fore the mechanism that causes natu­ rally occurring alcohol­induced flushing was discovered. ALDEHYDE DEHYDROGENASE DEFICIENCY Harada and colleagues directly related naturally occurring AS CAUSE OF FACIAL FLUSHING aldehyde dehydrogenase blockade to elevated acetaldehyde lev­ els and flushing. Wolff (1972) and others (Zeiner et al. 1979) REACTION TO ALCOHOL IN JAPANESE had observed that unmedicated Japanese and people from neigh­ boring regions of Asia often showed the same flushing response Commentary by David Goldman, M.D. after intake of relatively small quantities of alcohol. In 1981 Harada and colleagues Agarwal and Goedde showed that some KEY WORDS: aldehyde dehydrogenase; alcohol flush reaction; people were naturally deficient in the aldehyde dehydrogenase Asian; metabolism; acetaldehyde; genetics and heredity; enzyme (Agarwal et al. 1981). By using a technique (i.e., protein AOD dependence electrophoresis) that separates the enzyme in an electric field, ldehyde dehydrogenase is an enzyme responsible for the followed by a stain for the enzyme, they found that acetaldehyde A breakdown of acetaldehyde, a toxic intermediate produced dehydrogenase was structurally different in people in whom the directly from the metabolism of alcohol. Aldehyde dehydrogenase aldehyde dehydrogenase activity was deficient. One year later these researchers published their seminal letter to the editor of is extraordinarily efficient in keeping acetaldehyde levels very 48 ALCOHOL HEALTH & RESEARCH WORLD SEMINAL ARTICLES Lancet, relating findings that closed the link between the alde­ Much of the current excitement in alcohol research revolves hyde dehydrogenase enzyme deficiency and alcohol­induced around identifying genetic factors that, like ALDH2 , act to in­ flushing. People with the deficient aldehyde dehydrogenase were fluence a person’s vulnerability to alcohol but that act at the lev­ clearly shown to be those with high acetaldehyde levels after al­ el of the brain. Such factors may lead a person to seek alcohol cohol consumption. more avidly and respond to it with greater or lessor sensitivity. A cascade of research was triggered by the observations Intensive family studies, such as the National Institute on Harada and colleagues reported in this letter. The precise Al c o h o l A b u s e a n d Al co h o li sm’ s C o l labo r a ti v e St u d y o n d e m o n s t r a t i o n t h a t t h e f u n c t i o n a l d i f f e r e n c e i n a l c o h o l Genetics of Alcoholism (COGA), are underway to identify such metabolism in people with East Asian ancestry was attributable factors. Once the genes are identified, gene­environment and to a structural difference in ALDH2 led to studies of the enzyme gene­gene interaction studies will be required to better under­ protein and of the gene that determines this enzyme. It could be stand the forces that combine in the development of vulnerability said that, for alcoholism, the molecule of the 1980’s was alde­ for alcoholism. The epidemiological studies on ALDH2 show hyde dehydrogenase. Two years after this letter appeared, that such genetic factors act probabilistically rather than deter­ Yoshida and colleagues (1984) showed that the cause of ALDH2 ministically to influence alcoholism vulnerability. In other inactivation in East Asian subjects was a substitution of a single words, people with a genetic vulnerability factor may have a amino acid (i.e., lysine substituted for glutamate in position 487 higher probability of becoming alcoholics, but they are not pre­ of the protein chain). This amino acid substitution was itself destined to developing the disease. found to result from a single DNA base substitution among the What are the factors that influence some individuals to become t h o u s a n d s o f D N A b a s e s t h a t m a k e u p t h e A L D H 2 g e n e . alcoholics, even though they have aldehyde dehydrogenase defi­ Structurally, the aldehyde dehydrogenase enzyme is composed ciency? Studies of alcoholics who carry the protective aldehyde of four usually identical subunits (i.e., it is a tetramer). The dehydrogenase variant may reveal other genetic and nongenetic tetramer was found to be inactivated if even one of its four sub­ factors that lead to alcoholism or that are protective for alco­ units had the glutamate 487 substitution. It is for this reason that holism. Examples of gene­gene and gene­environmental influ­ the inactive variant of the gene, designated ALDH2 , follows a ences involving aldehyde dehydrogenase include the finding that dominant pattern of inheritance. For example, if the version of variations in alcohol dehydrogenase play an interacting role in al­ ALDH2 inherited from either one of an individual’s parents is coholism vulnerability (Thomasson et al. 1991) and the discovery ALDH2 , there is nearly a complete loss of aldehyde dehydroge­ that vulnerability to alcoholism is increased in East Asians who nase enzyme activity. Geneg ­ eography studies revealed that aldehyde dehydrogenase have immigrated to North America. ■ deficiency was highest in people from East Asia and absent or nearly absent in whites and blacks. DNAb ­ ased tests showed that D A V I D G O L D M A N , M.D. , i s d i r e c t o r o f t h e L a b o r a t o r y o f the DNA substitution responsible for the deficiency was the same Neurogenetics in the Division of Intramural Clinical and across populations and also within populations in which the defi­ Biological Research at the National Institute on Alcohol Abuse ciency is abundant. Epidemiological studies of populations with a and Alcoholism, Bethesda, Maryland. high prevalence of ALDH2 revealed that aldehyde dehydrogenase deficiency dramatically lowers vulnerability to alcoholism. In do­ ing so, ALDH2 deficiency interacts with other factors, including a REFERENCES common, superactive genetic variant of alcohol dehydrogenase AGARWAL, D.P.; HARADA, S.; AND GOEDDE, H.W. Racial differences in biological (ADH2 ) which increases the rate that acetaldehyde is produced. sensitivity to ethanol: The role of alcohol dehydrogenase and aldehyde dehydroge­ Thus, a single DNA nucleotide difference, present in hundreds of nase isozymes. Alcoholism: Clinical and Experimental Research 5:12–16, 1981. millions of people, profoundly influences their experiences with alcohol and vulnerability to alcoholism. HALD, J., AND JACOBSEN, E. The sensitizing effect of tetraethylthiuram disulphide A mark of good scientific paradigms is their propensity for (Antabuse) to ethyl alcohol. Lancet ii:1001–1004, 1948. shaping the future by posing answerable questions that open new intellectual vistas. For aldehyde dehydrogenase, many of the HARADA, S.; AGARWAL, D.P.; AND GOEDDE, H.W. Aldehyde dehydrogenase defi­ most interesting and humanistically most significant questions ci en c y a s ca use of fa c ia l flu s hi ng reac tio n to al c oho l in J ap an e se. Lancet remain unanswered. For example, what are the additional risks ii(8253):982, 1981. besides flushing for people with aldehyde dehydrogenase defi­ ciency who consume alcohol? This question is being intensively THOMASSON, H.R.; EDENBERG, H.J.; CRABB, D.; MAI, X.­L.; JEROME, R.E.; LI, explored in several ways, including comparing alcoholics with T.­K.; WANG, S.­P.; LIN, Y.­T.; LU, R.­B.; AND YIN, S.­J. Alcohol and aldehyde de­ and without liver disease. hydrogenase genotypes and alcoholism in Chinese men. American Journal of Researchers are only beginning to ask other important ques­ Human Genetics 48:677–681, 1991. tions. For example, why do East Asians so frequently have alde­ WOLFF, P. Ethnic differences in alcohol sensitivity. Science 125:449–451, 1972. hyde dehydrogenase deficiency—by chance or necessity (i.e., was there some biological [selective] advantage in ancient times and is YOSHIDA, A.; HUANG, I.Y.; AND IWAKA, M. Molecular abnormality of an inactive there any current advantage to possessing the ALDH2 gene)? Do aldehyde dehydrogenase variant commonly found in Orientals. Proceedings of the people who abstain from alcohol use suffer any negative conse­ National Academy of Sciences, USA 81:259–261, 1984. quences of aldehyde dehydrogenase deficiency? ZIENER, A.R.; PAREDES, A.; AND CHRISTENSEN, C.H. The role of acetaldehyde in A chemical compound formed as an intermediate step between the initial form mediating reactivity to an acute dose of alcohol among different racial groups. Alcoholism: Clinical and Experimental Research 3:11–18, 1979. (i.e., alcohol) and the final product (i.e., acetate). VOL. 19, NO. 1, 1995 49

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Published: Mar 1, 167

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