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Roles of defective ALDH2 polymorphism on liver protection and cancer development

Environmental Health and Preventive Medicine volume 21, pages 395–402 (2016)Cite this article

Abstract

Because serum transaminases elevate alcohol dose dependently as a consequence of liver injury, they serve as useful biological markers of excessive drinking. However, these markers are inadequate in individuals with a defective allele of the aldehyde dehydrogenase 2 gene, ALDH2*2, because they show a different correlation with the amount of ethanol. For example, the serum alanine aminotransferase (ALT) level could become even lower than the baseline after alcohol intake in ALDH2*2 carriers. In fact, multiple studies suggest that ALDH2*2 is a hepato-protective factor in healthy individuals. Importantly, excessive drinking is particularly dangerous in carriers of ALDH2*2 because the risk of alcohol-related cancer is much higher than that for ALDH2*1/*1 carriers. Without recognizing the genotype interaction on serum transaminase, the opportunity to warn people about potential cancer risks is missed owing to incorrect interpretation. This is particularly important in East Asian countries where approximately half of the population carries the ALDH2*2 allele. To date, the mechanism of liver protection from ethanol load in individuals with ALDH2*2 has not been fully elucidated. However, some reasonable mechanisms have been suggested by experimental studies, including remodelling of detoxifying systems. Further studies to uncover the whole mechanism are anticipated.

Introduction

A defective allele of the aldehyde dehydrogenase (ALDH) 2 gene, ALDH2*2 (rs671), is highly prevalent in East Asian countries [1, 2]. Although the mechanism is not well understood, ALDH2*2 has been reported to have positive and, surprisingly, negative associations with various kinds of diseases [3]. For example, the ALDH2*2 allele is suggested to be a risk factor of Alzheimer’s disease and osteoporosis according to epidemiological [4–6] and experimental studies [7–9]. By contrast, ALDH2*2 has also been reported to be a protective factor for essential hypertension [10–14] and psychiatric disorders, such as bipolar disorder [15], depression, and anxiety [16, 17].

We herein describe the function of ALDH2 and the pathophysiological impact of its defective polymorphism, ALDH2*2, with particular focus on its effects on cancer development and serum transaminase levels associated with ethanol intake. We also discuss the significance of ALDH2*2 on the value of serum transaminases as a biological marker of excessive drinking.

ALDH2

ALDHs catalyse the oxidation of many chemically diverse aldehydes to their corresponding acid metabolites. The ALDH superfamily plays an important role in the biotransformation of a variety of exogenous and endogenous aldehydes [18]. The human ALDH gene superfamily comprises 19 genes in 11 families and 4 subfamilies [19, 20].

One member of the ALDH superfamily, ALDH2, exhibits three types of enzyme activity: dehydrogenase, esterase, and reductase [21, 22]. The dehydrogenase activity requires the cofactor nicotinamide adenine dinucleotide (NAD+) and converts aldehydes to their respective carboxylic acids, e.g. acetaldehyde to acetic acid. The major lipid peroxidation products 4-hydroxy-2-nonenal (4HNE) and malondialdehyde (MDA) are also detoxified by ALDH2 [23, 24].

ALDH2 has the highest affinity for acetaldehyde, an important intermediary product of ethanol metabolism. Although acetaldehyde is also detoxified by other ALDH isozymes, including cytosolic ALDH1A1 and mitochondrial ALDH1B1, ALDH2 is the primary ALDH responsible for the clearance of ethanol-derived acetaldehyde [3, 18, 25].

ALDH2 polymorphism

Based on the National Center for Biotechnology Information database, nearly 300 single nucleotide polymorphisms (SNPs) have been reported for ALDH2. Of these, approximately 180 mutations are associated with amino acid replacement. However, r671 is the only SNP resulting in a powerful phenotypic change due to compromised protein function. The mutation site is located at exon 12, nucleotide position 42421 (transition of G to A), resulting in a Glu504 substitution to Lys. Glu504Lys in the precursor protein is also described as Glu487Lys in the mature protein form. The allele with this mutation is called ALDH2*2, in contrast to the wild type ALDH2*1.

The Glu487Lys mutation severely decreases ALDH enzymatic activity with respect to all three of its enzymatic functions (as a dehydrogenase, esterase, and reductase) [22, 26]. It is reported that this alteration in ALDH2 increases the Km value (the concentration at which the reaction rate is half the maximum rate) for NAD+ (the cofactor of ALDH2) by 150-fold compared to the wild type enzyme [27]. In fact, an ethanol challenge of Chinese volunteers was shown to elicit a 20-fold higher blood acetaldehyde level in the ALDH2*1/*2 subjects than in ALDH2*1/*1 subjects [28].

Effect of ALDH2*2 on drinking behaviour

The ALDH2*2 polymorphism strongly inhibits drinking behaviour [10, 29]. According to Peng et al. [28], ethanol administration caused a 50 % increase in heart rate and ‘terrible feelings’ in ALDH2*1/*2 subjects, commonly referred to as “flushing syndrome”, whereas no change was observed in ALDH2*1/*1 subjects. Given such vulnerability to drinking alcohol, it is not surprising that individuals with the ALDH2*2 allele tend not to be habitual drinkers.

However, the reinforcing properties of ethanol could overwhelm the uncomfortable symptoms of acetaldehyde; indeed, carriers of ALDH2*2 do still drink ethanol to a certain extent. For example, Nakamura et al. [30] reported the mean number of drinks per day of 2.4 ± 1.7 in ALDH2*1/*1 subjects, 1.7 ± 2.0 in ALDH2*1/*2 subjects, and 0.1 ± 0.4 in ALDH2*2/*2 subjects. Furthermore, alcoholics who carry ALDH2*1/*2 were reported to consume a comparable amount of ethanol to alcoholics with ALDH2*1/*1 [31].

Effect of ALDH2*2 on cancerous diseases

Accumulating evidence suggests that a drinking habit for an individual with the ALDH2*2 allele increases the risk of cancerous diseases, including upper aerodigestive, gastric, colorectal, hepatic, and lung cancer [32–47]. For example, it was reported that individuals with the ALDH2*1/*2 genotype who were heavy drinkers (≥46 g ethanol/day and ≥5 days/week) had a 38-fold greater risk of developing oesophageal cancer compared to non-drinking individuals with the ALDH2*1/*1 genotype, while drinkers with the ALDH2*1/*1 allele had only a 2-fold greater risk [47]. No increased risk was found in non-drinking ALDH2*1/*2 subjects (OR = 0.55, p = 0.226) (Fig. 1a).

Fig. 1
figure 1

Interaction between ALDH2 polymorphism and alcohol intake on oesophageal cancer risk and indicators of excessive drinking. a Estimated odds ratios (OR) for oesophageal cancer with adjustment for cumulative smoking level reported by Koyanagi and colleagues (a Japanese case–control study) [47]. The error bars represent 95 % confidence intervals. b Indicators of excessive drinking reported by Takeshita and colleagues (population-based study for Japanese workers) [57]. Data represent mean value. AST aspartate transaminase, ALT alanine transaminase

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It is well established that DNA adduct formation has an aetiological role in cancer [48]. We previously reported that acetaldehyde-derived DNA adducts are elevated to a greater extent in the liver and stomach of Aldh2 knockout mice following ethanol administration than in the liver and stomach of wild type mice [49, 50]. Similarly, Ishikawa and colleagues [51] showed that subjects carrying the ALDH2*2 allele who consumed ethanol more than three times per week had greater DNA damage, as reflected by an increased micronuclei frequency. Furthermore, cytochrome P450 (CYP2E1), which is known to form reactive oxygen species [52] and enhance pro-carcinogen activation [53], is upregulated in Aldh2 knockout mice, and is further induced by ethanol administration [54]. As such, ALDH2*2 has the potential to promote the risk of cancers induced by alcohol consumption (Fig. 1).

Effect of ALDH2*2 on indicators of excessive drinking

Serum alanine transaminase (ALT), aspartate aminotransaminase (AST), and gamma-glutamyltransferase (GGT) levels are generally used as biological markers of excessive drinking, which elevate dose dependently as a result of alcoholic liver injury [55, 56]. These markers have been presumed to be particularly high in drinkers that carry ALDH2*2, because this allele is expected to promote alcoholic liver injury. However, in reality, the opposite results have been obtained in multiple epidemiological and experimental studies.

Takeshita and colleagues [57] studied Japanese male workers who were free from hepatic viruses and from high transaminase activities (<100 IU/L), and showed that subjects with ALDH2*2 consuming moderate to high levels of alcohol had lower serum AST, ALT, and GGT levels (e.g. 25, 27, and 64 IU/L, respectively, in subjects with ALDH2*1/*1 versus 22, 17, and 42 IU/L, respectively, in subjects with ALDH2*1/*2) (Fig. 1b). Another study on Japanese male workers suggested that ALDH2*2 is an independent protective factor against elevation of the serum ALT level (odds ratio of 0.16) from multivariate logistic regression analysis, including body mass index and drinking habits in the model [58]. This finding was confirmed in a subsequent large-scale epidemiological study [10].

Furthermore, animal experiments using Aldh2 knockout mice showed the same tendency; serum ALT decreased after 5 weeks of simple ethanol loading (without any additional treatments to induce liver injury) in Aldh2 knockout mice, while no change was observed in wild type mice [59]. In a subsequent study, the decrease of ALT level in Aldh2 knockout mice was reported to be sustained for as long as the ethanol loading was administered, whereas wild type mice showed elevation of serum ALT [60]. Moreover, a liver injury model induced with a high-fat diet and carbon tetrachloride also showed lower serum ALT values in Aldh2 knockout mice than in wild type mice [61].

Mechanism of liver damage amelioration induced by congenital lack of ALDH2

Some mechanisms have been suggested to explain these observed interactions between the ALDH2 genotype and drinking on serum transaminase levels (Fig. 2). For example, the effects of ALDH2*2 on curbing acetaldehyde metabolism could produce benefits. Cyanamide, an ALDH inhibitor, diminished the ethanol-elicited increase of oxidative stress by inhibition of reduced nicotinamide adenine dinucleotide (NADH) formation in the mitochondria during the metabolism of acetaldehyde to acetate [62, 63]. This theory suggests that the ALDH2*2 allele can ameliorate the sharp increase of NADH that causes mitochondrial dysfunction, resulting in oxidative stress and hepatocyte damage from alcohol consumption. Supporting this hypothesis, Aldh2 knockout mice showed lower MDA and higher glutathione (GSH) levels after a single-dose administration of ethanol [64].

Fig. 2
figure 2

Proposed mechanism of amelioration of liver damage and aggravation of cancer development by a combination of alcohol intake and possession of a defective polymorphism of ALDH2 (ALDH2*2). ALDH2 aldehyde dehydrogenase 2, TNFα tumour necrosis factor-alpha, STAT3 signal transducer and activator of transcription 3

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Ethanol loading to people with ALDH2*2 might decrease tumour necrosis factor-alpha (TNFα) through inhibition of the associated transcription pathways (nuclear factor-kappa B pathway and mitogen-activated protein kinase pathway, which are considered to be important pathways for alcoholic liver injury [65–67]) [59, 68]. An in vivo experiment using Aldh2 knockout mice showed decreased serum ALT, TNFα, and extracellular signal-regulated kinase 2 levels after 5 weeks of ethanol administration, and significant correlations were observed among these three factors [59].

A different mechanism was suggested using liver injury models, in which interleukin-6-induced signal transducer and activator of transcription 3 relieve hepatic steatosis and result in lower serum ALT levels [61]. Supporting this finding, Yokoyama and colleagues [69] performed an epidemiological study on Japanese alcoholic men and reported that the serum triglyceride concentration was lower in ALDH2*1/*2 carriers than in ALDH2*1/*1 carriers (the least squares means adjusted for age and drinking amount were 103 and 113 mg/dL, respectively).

Another convincing explanation for these associations involves remodelling of stress response systems that are induced in a compensatory manner to mitigate the cytotoxicity of endogenous aldehydes. This is because individuals lacking ALDH2 will likely be exposed to higher levels of endogenous aldehydes from birth, such as 4HNE and MDA [23, 24], thereby requiring an alternate defence system. In fact, Aldh2 knockout mice had higher levels of heme oxidase 1, an essential defensive factor against cellular oxidative stress, without any pre-treatment [54]. Furthermore, it was reported that a series of GSH-producing enzymes was upregulated in ALDH2*2 targeting mice [70]. A higher GSH level in individuals with ALDH2*2 has been confirmed in humans according to a case–control study of children in China [71]. In this study, better clinical outcomes were reported for ALDH2*2 carriers, such as lower serum troponin level and shorter stay period in intensive care unit [71].

The compensatory protection system may protect ALDH2*2 carriers not only from alcoholic liver damage but also from other pathologies, including cancerous diseases. To the best of our knowledge, ALDH2*2 has not been reported as a cancerous risk factor for non-drinkers, in spite of the decreased metabolic ability for 4HNE, which is a well-known cancer initiator [72]. Interestingly, a recent epidemiological study in Taiwan demonstrated that ALDH2*2 was a protective factor of hepatocellular carcinoma (HCC) for patients with hepatitis B-positive cirrhosis [73]. In this study, HCC did not appear to be induced by alcohol; only 14 % of the subjects had a drinking habit and no association between drinking and HCC was found. The multivariate-adjusted hazard ratio of ALDH2*1/*2 for HCC development was calculated to be 0.35 when the ALDH2*1/*1 genotype was set as reference. This finding suggests that ALDH2*2 could be a protective factor for alcohol-independent HCC. Induction of anti-oxidative proteins might be one of the defence systems for HCC development. Another possible mechanism could be that possession of ALDH2*2 ameliorates PI3K/Akt pathway activation [74]. It is known that the PI3K/Akt pathway is hyper-activated in tumours, resulting in the promotion of malignant growth [75].

Such amelioration of liver damage conferred by ALDH2*2 may be limited to the type of injury. For example, the liver injury model mentioned above suggested protective effects such as inhibition of fatty degeneration; nevertheless, adverse effects were also reported, such as aggravation of the inflammatory response and fibrosis [61]. Simple ethanol administration does not cause such a marked discrepancy; however, hepatocyte ballooning was observed only in Aldh2 knockout mice in spite of their lower TNFα and serum ALT levels [59]. However, in practice, people who carry ALDH2*2 drink much less than the amount given to experimental animals (see “Effect of ALDH2*2 on drinking behaviour”). This may explain why epidemiological studies have only observed the advantageous aspect of ALDH2*2 for liver tissue function.

Conclusion: significance of the interaction between ALDH2 polymorphism and alcohol intake

Serum transaminase is a useful indicator of excessive drinking for self-monitoring by drinkers themselves and for their surrounding healthcare workers [55, 56]. However, it is less useful in people with ALDH2*2, because it does not elevate dose dependently with ethanol in the same manner as observed in people with ALDH2*1*1 (see Effect of ALDH2*2 on indicators of excessive drinking). As a result, the opportunity to warn people with ALDH2*2 of excessive drinking for the prevention of alcohol-related diseases, particularly cancerous diseases, could be lost when relying on only serum transaminase levels as a marker. Furthermore, individuals with ALDH2*2 have higher risks of cancer development (see Effect of ALDH2*2 on cancerous diseases). In other words, ALDH2*2 carriers need to be more strict about limiting or refraining from drinking than ALDH2*1*1 carriers, and serum transaminase is an inadequate indicator of excessive drinking for carriers of ALDH2*2. Thus, effective risk assessment and disease prevention require screening for ALDH2 genotype.

The influence of the ALDH2*2 allele on the value of serum transaminases and GGT as markers of excessive drinking could be modified in individuals with additional pathological conditions such as metabolic disorders of lipids and sugars. It would be useful to investigate this issue further in the future. Moreover, the interaction of ALDH2 polymorphism and alcohol intake on other alcohol-related diseases such as cardiovascular diseases and reproductive disorders should be well studied.

Abbreviations

ALDH2:

Aldehyde dehydrogenase 2

AST:

Aspartate aminotransferase

ALT:

Alanine transaminase

GGT:

Gamma-glutamyltransferase

4HNE:

4-hydroxy-2-nonenal

MDA:

Malondialdehyde

SNPs:

Single nucleotide polymorphisms

TNFα:

Tumour necrosis factor-alpha

GSH:

Glutathione

References

  1. Goedde HW, Agarwal DP, Fritze G, Meier-Tackmann D, Singh S, Beckmann G, et al. Distribution of ADH2 and ALDH2 genotypes in different populations. Hum Genet. 1992;88:344–6.

    Article  CAS  PubMed  Google Scholar 

  2. Li H, Borinskaya S, Yoshimura K, Kal’ina N, Marusin A, Stepanov VA, et al. Refined geographic distribution of the oriental ALDH2*504Lys (nee 487Lys) variant. Ann Hum Genet. 2009;73:335–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Matsumoto A. Fundamental Properties of Aldehyde Dehydrogenase 2 (ALDH2) and the Importance of the ALDH2 Polymorphism. Nihon Eiseigaku Zasshi. 2016;71:55–68.

    Article  PubMed  Google Scholar 

  4. Kamino K, Nagasaka K, Imagawa M, Yamamoto H, Yoneda H, Ueki A, et al. Deficiency in mitochondrial aldehyde dehydrogenase increases the risk for late-onset Alzheimer’s disease in the Japanese population. Biochem Biophys Res Commun. 2000;273:192–6.

    Article  CAS  PubMed  Google Scholar 

  5. Wang B, Wang J, Zhou S, Tan S, He X, Yang Z, et al. The association of mitochondrial aldehyde dehydrogenase gene (ALDH2) polymorphism with susceptibility to late-onset Alzheimer’s disease in Chinese. J Neurol Sci. 2008;268:172–5.

    Article  CAS  PubMed  Google Scholar 

  6. Yamaguchi J, Hasegawa Y, Kawasaki M, Masui T, Kanoh T, Ishiguro N, et al. ALDH2 polymorphisms and bone mineral density in an elderly Japanese population. Osteoporos Int. 2006;17:908–13.

    Article  CAS  PubMed  Google Scholar 

  7. D’Souza Y, Elharram A, Soon-Shiong R, Andrew RD, Bennett BM. Characterization of Aldh2 mice as an age-related model of cognitive impairment and Alzheimer’s disease. Mol Brain. 2015;8:27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Shimizu Y, Sakai A, Menuki K, Mori T, Isse T, Oyama T, et al. Reduced bone formation in alcohol-induced osteopenia is associated with elevated p21 expression in bone marrow cells in aldehyde dehydrogenase 2-disrupted mice. Bone. 2011;48:1075–86.

    Article  CAS  PubMed  Google Scholar 

  9. Hoshi H, Hao W, Fujita Y, Funayama A, Miyauchi Y, Hashimoto K, et al. Aldehyde-stress resulting from Aldh2 mutation promotes osteoporosis due to impaired osteoblastogenesis. J Bone Miner Res. 2012;27:2015–23.

    Article  CAS  PubMed  Google Scholar 

  10. Takeuchi F, Isono M, Nabika T, Katsuya T, Sugiyama T, Yamaguchi S, et al. Confirmation of ALDH2 as a Major locus of drinking behavior and of its variants regulating multiple metabolic phenotypes in a Japanese population. Circ J. 2011;75:911–8.

    Article  CAS  PubMed  Google Scholar 

  11. Kato N, Takeuchi F, Tabara Y, Kelly TN, Go MJ, Sim X, et al. Meta-analysis of genome-wide association studies identifies common variants associated with blood pressure variation in east Asians. Nat Genet. 2011;43:531–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wang Y, Zhang Y, Zhang J, Tang X, Qian Y, Gao P, et al. Association of a functional single-nucleotide polymorphism in the ALDH2 gene with essential hypertension depends on drinking behavior in a Chinese Han population. J Hum Hypertens 2012;27:181–6.

  13. Takagi S, Baba S, Iwai N, Fukuda M, Katsuya T, Higaki J, et al. The aldehyde dehydrogenase 2 gene is a risk factor for hypertension in Japanese but does not alter the sensitivity to pressor effects of alcohol: the Suita study. Hypertens Res. 2001;24:365–70.

    Article  CAS  PubMed  Google Scholar 

  14. Amamoto K, Okamura T, Tamaki S, Kita Y, Tsujita Y, Kadowaki T, et al. Epidemiologic study of the association of low-Km mitochondrial acetaldehyde dehydrogenase genotypes with blood pressure level and the prevalence of hypertension in a general population. Hypertens Res. 2002;25:857–64.

    Article  CAS  PubMed  Google Scholar 

  15. Lee SY, Chen SL, Chang YH, Chen SH, Chu CH, Huang SY, et al. The ALDH2 and DRD2/ANKK1 genes interacted in bipolar II but not bipolar I disorder. Pharmacogenet Genom. 2010;20:500–6.

    Article  CAS  Google Scholar 

  16. Yoshimasu K, Mure K, Hashimoto M, Takemura S, Tsuno K, Hayashida M, et al. Genetic alcohol sensitivity regulated by ALDH2 and ADH1B polymorphisms as indicator of mental disorders in Japanese employees. Alcohol Alcohol. 2015;50:39–45.

    Article  PubMed  Google Scholar 

  17. Yoshimasu K, Mure K, Hashimoto M, Takemura S, Tsuno K, Hayashida M, et al. Genetic alcohol sensitivity regulated by ALDH2 and ADH1B polymorphisms is strongly associated with depression and anxiety in Japanese employees. Drug Alcohol Depend. 2015;147:130–6.

    Article  CAS  PubMed  Google Scholar 

  18. Vasiliou V, Pappa A, Estey T. Role of human aldehyde dehydrogenases in endobiotic and xenobiotic metabolism. Drug Metab Rev. 2004;36:279–99.

    Article  CAS  PubMed  Google Scholar 

  19. Vasiliou V, Bairoch A, Tipton KF, Nebert DW. Eukaryotic aldehyde dehydrogenase (ALDH) genes: human polymorphisms, and recommended nomenclature based on divergent evolution and chromosomal mapping. Pharmacogenetics. 1999;9:421–34.

    Article  CAS  PubMed  Google Scholar 

  20. Jackson B, Brocker C, Thompson DC, Black W, Vasiliou K, Nebert DW, et al. Update on the aldehyde dehydrogenase gene (ALDH) superfamily. Hum Genom. 2011;5:283–303.

    Article  CAS  Google Scholar 

  21. Wenzel P, Hink U, Oelze M, Schuppan S, Schaeuble K, Schildknecht S, et al. Role of reduced lipoic acid in the redox regulation of mitochondrial aldehyde dehydrogenase (ALDH-2) activity. Implications for mitochondrial oxidative stress and nitrate tolerance. J Biol Chem. 2007;282:792–9.

    Article  CAS  PubMed  Google Scholar 

  22. Larson HN, Zhou J, Chen Z, Stamler JS, Weiner H, Hurley TD. Structural and functional consequences of coenzyme binding to the inactive asian variant of mitochondrial aldehyde dehydrogenase: roles of residues 475 and 487. J Biol Chem. 2007;282:12940–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Brichac J, Ho KK, Honzatko A, Wang R, Lu X, Weiner H, et al. Enantioselective oxidation of trans-4-hydroxy-2-nonenal is aldehyde dehydrogenase isozyme and Mg2+ dependent. Chem Res Toxicol. 2007;20:887–95.

    Article  CAS  PubMed  Google Scholar 

  24. Yoval-Sanchez B, Rodriguez-Zavala JS. Differences in susceptibility to inactivation of human aldehyde dehydrogenases by lipid peroxidation byproducts. Chem Res Toxicol. 2012;25:722–9.

    Article  CAS  PubMed  Google Scholar 

  25. Yoshida A, Hsu LC, Yasunami M. Genetics of human alcohol-metabolizing enzymes. Prog Nucl Acid Res Mol Biol. 1991;40:255–87.

    Article  CAS  Google Scholar 

  26. Yoshida A, Huang IY, Ikawa M. Molecular abnormality of an inactive aldehyde dehydrogenase variant commonly found in Orientals. Proc Natl Acad Sci U S A. 1984;81:258–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Farres J, Wang X, Takahashi K, Cunningham SJ, Wang TT, Weiner H. Effects of changing glutamate 487 to lysine in rat and human liver mitochondrial aldehyde dehydrogenase. A model to study human (Oriental type) class 2 aldehyde dehydrogenase. J Biol Chem. 1994;269:13854–60.

    CAS  PubMed  Google Scholar 

  28. Peng GS, Chen YC, Tsao TP, Wang MF, Yin SJ. Pharmacokinetic and pharmacodynamic basis for partial protection against alcoholism in Asians, heterozygous for the variant ALDH2*2 gene allele. Pharmacogenet Genom. 2007;17:845–55.

    Article  CAS  Google Scholar 

  29. Matsuo K, Wakai K, Hirose K, Ito H, Saito T, Tajima K. Alcohol dehydrogenase 2 His47Arg polymorphism influences drinking habit independently of aldehyde dehydrogenase 2 Glu487Lys polymorphism: analysis of 2,299 Japanese subjects. Cancer Epidemiol Biomark Prev. 2006;15:1009–13.

    Article  CAS  Google Scholar 

  30. Nakamura Y, Amamoto K, Tamaki S, Okamura T, Tsujita Y, Ueno Y, et al. Genetic variation in aldehyde dehydrogenase 2 and the effect of alcohol consumption on cholesterol levels. Atherosclerosis. 2002;164:171–7.

    Article  CAS  PubMed  Google Scholar 

  31. Yokoyama A, Yokoyama T, Brooks PJ, Mizukami T, Matsui T, Kimura M, et al. Macrocytosis, macrocytic anemia, and genetic polymorphisms of alcohol dehydrogenase-1B and aldehyde dehydrogenase-2 in Japanese alcoholic men. Alcohol Clin Exp Res. 2014;38:1237–46.

    Article  CAS  PubMed  Google Scholar 

  32. Chen YJ, Chen C, Wu DC, Lee CH, Wu CI, Lee JM, et al. Interactive effects of lifetime alcohol consumption and alcohol and aldehyde dehydrogenase polymorphisms on esophageal cancer risks. Int J Cancer. 2006;119:2827–31.

    Article  CAS  PubMed  Google Scholar 

  33. Cui R, Kamatani Y, Takahashi A, Usami M, Hosono N, Kawaguchi T, et al. Functional variants in ADH1B and ALDH2 coupled with alcohol and smoking synergistically enhance esophageal cancer risk. Gastroenterology. 2009;137:1768–75.

    Article  CAS  PubMed  Google Scholar 

  34. Hiyama T, Yoshihara M, Tanaka S, Chayama K. Genetic polymorphisms and esophageal cancer risk. Int J Cancer. 2007;121:1643–58.

    Article  CAS  PubMed  Google Scholar 

  35. Guo YM, Wang Q, Liu YZ, Chen HM, Qi Z, Guo QH. Genetic polymorphisms in cytochrome P4502E1, alcohol and aldehyde dehydrogenases and the risk of esophageal squamous cell carcinoma in Gansu Chinese males. World J Gastroenterol. 2008;14:1444–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yokoyama A, Omori T, Yokoyama T, Tanaka Y, Mizukami T, Matsushita S, et al. Esophageal melanosis, an endoscopic finding associated with squamous cell neoplasms of the upper aerodigestive tract, and inactive aldehyde dehydrogenase-2 in alcoholic Japanese men. J Gastroenterol. 2005;40:676–84.

    Article  PubMed  Google Scholar 

  37. Yokoyama A, Mizukami T, Yokoyama T. Genetic polymorphisms of alcohol dehydrogense-1B and aldehyde dehydrogenase-2, alcohol flushing, mean corpuscular volume, and aerodigestive tract neoplasia in Japanese drinkers. Adv Exp Med Biol. 2015;815:265–79.

    Article  PubMed  Google Scholar 

  38. Yokoyama A, Muramatsu T, Ohmori T, Yokoyama T, Okuyama K, Takahashi H, et al. Alcohol-related cancers and aldehyde dehydrogenase-2 in Japanese alcoholics. Carcinogenesis. 1998;19:1383–7.

    Article  CAS  PubMed  Google Scholar 

  39. Yokoyama A, Yokoyama T, Omori T, Matsushita S, Mizukami T, Takahashi H, et al. Helicobacter pylori, chronic atrophic gastritis, inactive aldehyde dehydrogenase-2, macrocytosis and multiple upper aerodigestive tract cancers and the risk for gastric cancer in alcoholic Japanese men. J Gastroenterol Hepatol. 2007;22:210–7.

    Article  CAS  PubMed  Google Scholar 

  40. Hidaka A, Sasazuki S, Matsuo K, Ito H, Sawada N, Shimazu T, et al. Genetic polymorphisms of ADH1B, ADH1C and ALDH2, alcohol consumption, and the risk of gastric cancer: the Japan Public Health Center-based prospective study. Carcinogenesis. 2015;36:223–31.

    Article  CAS  PubMed  Google Scholar 

  41. Murata M, Tagawa M, Watanabe S, Kimura H, Takeshita T, Morimoto K. Genotype difference of aldehyde dehydrogenase 2 gene in alcohol drinkers influences the incidence of Japanese colorectal cancer patients. Jpn J Cancer Res. 1999;90:711–9.

    Article  CAS  PubMed  Google Scholar 

  42. Kato S, Tajiri T, Matsukura N, Matsuda N, Taniai N, Mamada H, et al. Genetic polymorphisms of aldehyde dehydrogenase 2, cytochrome p450 2E1 for liver cancer risk in HCV antibody-positive japanese patients and the variations of CYP2E1 mRNA expression levels in the liver due to its polymorphism. Scand J Gastroenterol. 2003;38:886–93.

    Article  CAS  PubMed  Google Scholar 

  43. Munaka M, Kohshi K, Kawamoto T, Takasawa S, Nagata N, Itoh H, et al. Genetic polymorphisms of tobacco- and alcohol-related metabolizing enzymes and the risk of hepatocellular carcinoma. J Cancer Res Clin Oncol. 2003;129:355–60.

    Article  CAS  PubMed  Google Scholar 

  44. Sakamoto T, Hara M, Higaki Y, Ichiba M, Horita M, Mizuta T, et al. Influence of alcohol consumption and gene polymorphisms of ADH2 and ALDH2 on hepatocellular carcinoma in a Japanese population. Int J Cancer. 2006;118:1501–7.

    Article  CAS  PubMed  Google Scholar 

  45. Abe H, Aida Y, Seki N, Sugita T, Tomita Y, Nagano T, et al. Aldehyde dehydrogenase 2 polymorphism influences development to hepatocellular carcinoma in East Asian alcoholic liver cirrhosis. J Gastroenterol Hepatol 2015;30:1376–83.

  46. Minegishi Y, Tsukino H, Muto M, Goto K, Gemma A, Tsugane S, et al. Susceptibility to lung cancer and genetic polymorphisms in the alcohol metabolite-related enzymes alcohol dehydrogenase 3, aldehyde dehydrogenase 2, and cytochrome P450 2E1 in the Japanese population. Cancer. 2007;110:353–62.

    Article  CAS  PubMed  Google Scholar 

  47. Koyanagi YN, Ito H, Oze I, Hosono S, Tanaka H, Abe T, et al. Development of a prediction model and estimation of cumulative risk for upper aerodigestive tract cancer on the basis of the aldehyde dehydrogenase 2 genotype and alcohol consumption in a Japanese population. Eur J Cancer Prev 2016. doi:10.1097/CEJ.0000000000000222.

  48. Pelkonen O, Nebert DW. Metabolism of polycyclic aromatic hydrocarbons: etiologic role in carcinogenesis. Pharmacol Rev. 1982;34:189–222.

    CAS  PubMed  Google Scholar 

  49. Matsuda T, Matsumoto A, Uchida M, Kanaly RA, Misaki K, Shibutani S, et al. Increased formation of hepatic N2-ethylidene-2’-deoxyguanosine DNA adducts in aldehyde dehydrogenase 2-knockout mice treated with ethanol. Carcinogenesis. 2007;28:2363–6.

    Article  CAS  PubMed  Google Scholar 

  50. Nagayoshi H, Matsumoto A, Nishi R, Kawamoto T, Ichiba M, Matsuda T. Increased formation of gastric N(2)-ethylidene-2’-deoxyguanosine DNA adducts in aldehyde dehydrogenase-2 knockout mice treated with ethanol. Mutat Res. 2009;673:74–7.

    Article  CAS  PubMed  Google Scholar 

  51. Ishikawa H, Miyatsu Y, Kurihara K, Yokoyama K. Gene-environmental interactions between alcohol-drinking behavior and ALDH2 and CYP2E1 polymorphisms and their impact on micronuclei frequency in human lymphocytes. Mutat Res. 2006;594:1–9.

    Article  CAS  PubMed  Google Scholar 

  52. Lu Y, Cederbaum AI. CYP2E1 and oxidative liver injury by alcohol. Free Radic Biol Med. 2008;44:723–38.

    Article  CAS  PubMed  Google Scholar 

  53. He X, Feng S. Role of metabolic enzymes P450 (CYP) on activating procarcinogen and their polymorphisms on the risk of cancers. Curr Drug Metab. 2015;16:850–63.

    Article  CAS  PubMed  Google Scholar 

  54. Matsumoto A, Thompson D, Chen Y, Vasiliou V, Kawamoto T, Ichiba M. Heme oxygenase 1 protects ethanol-administered liver tissue in Aldh2 knockout mice. Alcohol. 2016;52:49–54.

    Article  CAS  PubMed  Google Scholar 

  55. Giboney PT. Mildly elevated liver transaminase levels in the asymptomatic patient. Am Fam Physician. 2005;71:1105–10.

    PubMed  Google Scholar 

  56. Sharpe PC, McBride R, Archbold GP. Biochemical markers of alcohol abuse. QJM. 1996;89:137–44.

    Article  CAS  PubMed  Google Scholar 

  57. Takeshita T, Yang X, Morimoto K. The ALDH2 genotype, alcohol intake, and liver-function biomarkers among Japanese male workers. Hum Genet. 2000;106:589–93.

    Article  CAS  PubMed  Google Scholar 

  58. Murata C, Watanabe T, Furuya H, Sugioka Y, Mikurube H, Yokoyama A, et al. Aldehyde dehydrogenase 2 and beta 3-adrenergic receptor gene polymorphisms: their association with elevated liver enzymes and metabolic syndrome. Metabolism. 2003;52:1096–101.

    Article  CAS  PubMed  Google Scholar 

  59. Matsumoto A, Kawamoto T, Mutoh F, Isse T, Oyama T, Kitagawa K, et al. Effects of 5-week ethanol feeding on the liver of aldehyde dehydrogenase 2 knockout mice. Pharmacogenet Genom. 2008;18:847–52.

    Article  CAS  Google Scholar 

  60. Matsumoto A, Vasiliou V, Kawamoto T, Tanaka K, Ichiba M. Ethanol reduces lifespan, body weight, and serum alanine aminotransferase level of aldehyde dehydrogenase 2 knockout mouse. Alcohol Clin Exp Res. 2014;38:1883–93.

    Article  CAS  PubMed  Google Scholar 

  61. Kwon HJ, Won YS, Park O, Chang B, Duryee MJ, Thiele GE, et al. Aldehyde dehydrogenase 2 deficiency ameliorates alcoholic fatty liver but worsens liver inflammation and fibrosis in mice. Hepatology. 2014;60:146–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Bailey SM, Cunningham CC. Effect of dietary fat on chronic ethanol-induced oxidative stress in hepatocytes. Alcohol Clin Exp Res. 1999;23:1210–8.

    Article  CAS  PubMed  Google Scholar 

  63. Bailey SM, Cunningham CC. Acute and chronic ethanol increases reactive oxygen species generation and decreases viability in fresh, isolated rat hepatocytes. Hepatology. 1998;28:1318–26.

    Article  CAS  PubMed  Google Scholar 

  64. Matsumoto A, Ichiba M, Horita M, Yamashita Z, Takahashi T, Isse T, et al. Lack of aldehyde dehydrogenase ameliorates oxidative stress induced by single-dose ethanol administration in mouse liver. Alcohol. 2007;41:57–9.

    Article  CAS  PubMed  Google Scholar 

  65. Louvet A, Mathurin P. Alcoholic liver disease: mechanisms of injury and targeted treatment. Nat Rev Gastroenterol Hepatol. 2015;12:231–42.

    Article  PubMed  Google Scholar 

  66. Gao B, Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology. 2011;141:1572–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Aroor AR, Jackson DE, Shukla SD. Elevated activation of ERK1 and ERK2 accompany enhanced liver injury following alcohol binge in chronically ethanol-fed rats. Alcohol Clin Exp Res. 2011;35:2128–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Lindros KO, Jokelainen K, Nanji AA. Acetaldehyde prevents nuclear factor-kappa B activation and hepatic inflammation in ethanol-fed rats. Lab Invest. 1999;79:799–806.

    CAS  PubMed  Google Scholar 

  69. Yokoyama A, Yokoyama T, Matsui T, Mizukami T, Kimura M, Matsushita S, et al. Alcohol dehydrogenase-1B (rs1229984) and aldehyde dehydrogenase-2 (rs671) genotypes are strong determinants of the serum triglyceride and cholesterol levels of Japanese alcoholic men. PLoS One. 2015;10:e0133460.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Endo J, Sano M, Katayama T, Hishiki T, Shinmura K, Morizane S, et al. Metabolic remodeling induced by mitochondrial aldehyde stress stimulates tolerance to oxidative stress in the heart. Circ Res. 2009;105:1118–27.

    Article  CAS  PubMed  Google Scholar 

  71. Zhang H, Gong DX, Zhang YJ, Li SJ, Hu S. Effect of mitochondrial aldehyde dehydrogenase-2 genotype on cardioprotection in patients with congenital heart disease. Eur Heart J. 2012;33:1606–14.

    Article  CAS  PubMed  Google Scholar 

  72. Zhong H, Yin H. Role of lipid peroxidation derived 4-hydroxynonenal (4-HNE) in cancer: focusing on mitochondria. Redox Biol. 2015;4:193–9.

    Article  CAS  PubMed  Google Scholar 

  73. Chien J, Liu J, Lee MH, Jen CL, Batrla-Utermann R, Lu SN, et al. Risk and Predictors of Hepatocellular Carcinoma for Chronic Hepatitis b Patients With Newly Developed Cirrhosis. J Gastroenterol Hepatol 2016. doi:10.1111/jgh.13422.

  74. Xia G, Fan F, Liu M, Wang S, Wu J, Shen C, et al. Aldehyde dehydrogenase 2 deficiency blunts compensatory cardiac hypertrophy through modulating Akt phosphorylation early after transverse aorta constriction in mice. Biochim Biophys Acta. 2016;1862:1587–93.

    Article  CAS  PubMed  Google Scholar 

  75. Danielsen SA, Eide PW, Nesbakken A, Guren T, Leithe E, Lothe RA. Portrait of the PI3K/AKT pathway in colorectal cancer. Biochim Biophys Acta. 2015;1855:104–21.

    CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by JSPS Grant-in-Aid for Young Scientists (B) Grant Number 25870515.

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Authors and Affiliations

  1. Department of Social Medicine, Saga University School of Medicine, Saga, 849-8501, Japan

    Akiko Matsumoto

  2. Department of Clinical Pharmacy, University of Colorado School of Pharmacy, 12850 E. Aurora, Denver, CO, 80045, USA

    David C. Thompson

  3. Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, 06520-8034, USA

    Ying Chen & Vasilis Vasiliou

  4. Department of Molecular Biology, Hamamatsu University School of Medicine, Hamamatsu, 431-3125, Japan

    Kyoko Kitagawa

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  1. Akiko Matsumoto
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  5. Vasilis Vasiliou
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Correspondence to Akiko Matsumoto.

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Matsumoto, A., Thompson, D.C., Chen, Y. et al. Roles of defective ALDH2 polymorphism on liver protection and cancer development. Environ Health Prev Med 21, 395–402 (2016). https://doi.org/10.1007/s12199-016-0579-2

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  • DOI: https://doi.org/10.1007/s12199-016-0579-2

Keywords

Environmental Health and Preventive Medicine

ISSN: 1347-4715

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