Polymorphisms in the promoter region of the human class II alcohol dehydrogenase (ADH4) gene affect both transcriptional activity and ethanol metabolism in Japanese subjects

Kimura, Yukiko; Nishimura, Fusae; Abe, Shuntaro; Fukunaga, Tetsuo; Tanii, Hideji; Saijoh, Kiyofumi

doi:10.2131/jts.34.89

Cited by 15 publications

(16 citation statements)

References 27 publications

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“…Downregulation of these genes may represent a state where the hepatocytes shift their balance from metabolism to regeneration. Examples are CPS1, the first enzyme of the urea cycle and key factor of ammonia detoxification (Simmer et al 1990;Schliess et al 2014); PCK1 as a main control enzyme of gluconeogenesis (Pilz et al 1992); SLC2A2, also known as the glucose carrier GLUT2 (Froguel et al 1991); CYP8B1, a key enzyme in bile acid metabolism (Gåfvels et al 1999); CYP4A11, the major fatty acid omegahydroxylase, which is involved in controlling the balance of lipids (Antoun et al 2006); ABCA8, one of the liver's ABC transporters (Tsuruoka et al 2002); and ADH4, an aldehyde dehydrogenase that metabolizes numerous substrates, including retinol, hydroxysteroids, and also ethanol (Kimura et al 2009). Such complex but stereotypical patterns of gene deregulation induced by a chemical can also be interpreted as a situation of disturbed hepatocyte physiology and could be the result of different insults to the liver.…”

Section: Human Disease Genesmentioning

confidence: 99%

Toxicogenomics directory of chemically exposed human hepatocytes

et al. 2014

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A long-term goal of numerous research projects is to identify biomarkers for in vitro systems predicting toxicity in vivo. Often, transcriptomics data are used to identify candidates for further evaluation. However, a systematic directory summarizing key features of chemically influenced genes in human hepatocytes is not yet available. To bridge this gap, we used the Open TG-GATES database with Affymetrix files of cultivated human hepatocytes incubated with chemicals, further sets of gene array data with hepatocytes from human donors generated in this study, and publicly available genome-wide datasets of human liver tissue from patients with non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular cancer (HCC). After a curation procedure, expression data of 143 chemicals were included into a comprehensive biostatistical analysis. The results are summarized in the publicly available toxicotranscriptomics directory (http://wiki.toxbank.net/toxicogenomics-map/) which provides information for all genes whether they are up- or downregulated by chemicals and, if yes, by which compounds. The directory also informs about the following key features of chemically influenced genes: (1) Stereotypical stress response. When chemicals induce strong expression alterations, this usually includes a complex but highly reproducible pattern named 'stereotypical response.' On the other hand, more specific expression responses exist that are induced only by individual compounds or small numbers of compounds. The directory differentiates if the gene is part of the stereotypical stress response or if it represents a more specific reaction. (2) Liver disease-associated genes. Approximately 20 % of the genes influenced by chemicals are up- or downregulated, also in liver disease. Liver disease genes deregulated in cirrhosis, HCC, and NASH that overlap with genes of the aforementioned stereotypical chemical stress response include CYP3A7, normally expressed in fetal liver; the phase II metabolizing enzyme SULT1C2; ALDH8A1, known to generate the ligand of RXR, one of the master regulators of gene expression in the liver; and several genes involved in normal liver functions: CPS1, PCK1, SLC2A2, CYP8B1, CYP4A11, ABCA8, and ADH4. (3) Unstable baseline genes. The process of isolating and the cultivation of hepatocytes was sufficient to induce some stress leading to alterations in the expression of genes, the so-called unstable baseline genes. (4) Biological function. Although more than 2,000 genes are transcriptionally influenced by chemicals, they can be assigned to a relatively small group of biological functions, including energy and lipid metabolism, inflammation and immune response, protein modification, endogenous and xenobiotic metabolism, cytoskeletal organization, stress response, and DNA repair. In conclusion, the introduced toxicotranscriptomics directory offers a basis for a rationale choice of candidate genes for biomarker evaluation studies and represents an easy to use source of background information on chemically infl...

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Section: Human Disease Genesmentioning

confidence: 99%

Toxicogenomics directory of chemically exposed human hepatocytes

et al. 2014

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“…On the other hand, human ADH2 is known to be highly active towards ethanol [54], and is suggested to contribute to alcohol metabolism [55,56]. However, its contribution possibility to systemic alcohol metabolism may become lower in habitual drinking, because ADH2 activity has been demonstrated to be decreased in baboon liver by moderate drinking and to be almost abolished by heavy drinking [57].…”

Section: Other Adh Isozymes In Alcohol Metabolismmentioning

confidence: 99%

A New View of Alcohol Metabolism and Alcoholism—Role of the High-Km Class Ⅲ Alcohol Dehydrogenase (ADH3)

Haseba

Ohno

2010

IJERPH

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The conventional view is that alcohol metabolism is carried out by ADH1 (Class I) in the liver. However, it has been suggested that another pathway plays an important role in alcohol metabolism, especially when the level of blood ethanol is high or when drinking is chronic. Over the past three decades, vigorous attempts to identify the enzyme responsible for the non-ADH1 pathway have focused on the microsomal ethanol oxidizing system (MEOS) and catalase, but have failed to clarify their roles in systemic alcohol metabolism. Recently, using ADH3-null mutant mice, we demonstrated that ADH3 (Class III), which has a high Km and is a ubiquitous enzyme of ancient origin, contributes to systemic alcohol metabolism in a dose-dependent manner, thereby diminishing acute alcohol intoxication. Although the activity of ADH3 toward ethanol is usually low in vitro due to its very high Km, the catalytic efficiency (kcat/Km) is markedly enhanced when the solution hydrophobicity of the reaction medium increases. Activation of ADH3 by increasing hydrophobicity should also occur in liver cells; a cytoplasmic solution of mouse liver cells was shown to be much more hydrophobic than a buffer solution when using Nile red as a hydrophobicity probe. When various doses of ethanol are administered to mice, liver ADH3 activity is dynamically regulated through induction or kinetic activation, while ADH1 activity is markedly lower at high doses (3–5 g/kg). These data suggest that ADH3 plays a dynamic role in alcohol metabolism, either collaborating with ADH1 or compensating for the reduced role of ADH1. A complex two-ADH model that ascribes total liver ADH activity to both ADH1 and ADH3 explains the dose-dependent changes in the pharmacokinetic parameters (β, CLT, AUC) of blood ethanol very well, suggesting that alcohol metabolism in mice is primarily governed by these two ADHs. In patients with alcoholic liver disease, liver ADH3 activity increases, while ADH1 activity decreases, as alcohol intake increases. Furthermore, ADH3 is induced in damaged cells that have greater hydrophobicity, whereas ADH1 activity is lower when there is severe liver disease. These data suggest that chronic binge drinking and the resulting liver disease shifts the key enzyme in alcohol metabolism from low-Km ADH1 to high-Km ADH3, thereby reducing the rate of alcohol metabolism. The interdependent increase in the ADH3/ADH1 activity ratio and AUC may be a factor in the development of alcoholic liver disease. However, the adaptive increase in ADH3 sustains alcohol metabolism, even in patients with alcoholic liver cirrhosis, which makes it possible for them to drink themselves to death. Thus, the regulation of ADH3 activity may be important in preventing alcoholism development.

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“…Similarly, the ADH1B*3 allele (rs2066702, located in exon 9 of ADH1B ) results in an arginine to cysteine change (Carr et al, 1989) that has shown a protective association in the development of alcohol dependence in samples of African descent (Edenberg et al, 2006; Ehlers et al, 2001a, 2007; Luo et al, 2006; McCarthy et al, 2010) and a subset of the Native American population described in the present study (Wall et al, 2003). More recently, researchers have begun to study the remaining ADH genes to evaluate whether variants in these genes might also be related to alcohol dependence and related phenotypes (e.g., Birley et al, 2009; Hall et al, 2007; Han et al, 2007; Kuo et al, 2008; Luo et al, 2007; Sherva et al, 2009; van Beek et al, 2010), with several of these studies reporting evidence of association with ADH4 (Edenberg et al, 2006; Guindalini et al, 2005; Kimura et al, 2009; Luo et al, 2005; MacGregor et al, 2009; Preuss et al, 2011) as well as with ADH1A and ADH1B (Edenberg et al, 2006). …”

Section: Introductionmentioning

confidence: 99%

Association of Alcohol Dehydrogenase Genes with Alcohol-Related Phenotypes in a Native American Community Sample

Gizer

Edenberg

Gilder

et al. 2011

Alcoholism: Clinical and Experimental Research

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Background Previous linkage studies, including a study of the Native American population described in the present report, have provided evidence for linkage of alcohol dependence and related traits to chromosome 4q near a cluster of alcohol dehydrogenase (ADH) genes, which encode enzymes of alcohol metabolism. Methods The present study tested for associations between alcohol dependence and related traits and 22 single nucleotide polymorphisms (SNPs) spanning the seven ADH genes. Participants included 586 adult men and women recruited from eight contiguous Native American reservations. A structured interview was used to assess DSM-III-R alcohol dependence criteria as well as a set of severe alcohol misuse symptoms and alcohol withdrawal symptoms. Results No evidence for association with the alcohol dependence diagnosis was observed, but a SNP in exon 9 of ADH1B (rs2066702; ADH1B*3) and a SNP at the 5' end of ADH4 (rs3762894) showed significant evidence of association with the presence of withdrawal symptoms (p=0.0018 and 0.0012, respectively). Further, a haplotype analysis of these two SNPs suggested haplotypes containing either of the minor alleles were protective against alcohol withdrawal relative to the ancestral haplotype (p=0.000006). Conclusions These results suggest that variants in the ADH1B and ADH4 genes may be protective against the development of some symptoms associated with alcohol dependence.

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Polymorphisms in the promoter region of the human class II alcohol dehydrogenase (ADH4) gene affect both transcriptional activity and ethanol metabolism in Japanese subjects

Cited by 15 publications

References 27 publications

Toxicogenomics directory of chemically exposed human hepatocytes

Toxicogenomics directory of chemically exposed human hepatocytes

A New View of Alcohol Metabolism and Alcoholism—Role of the High-Km Class Ⅲ Alcohol Dehydrogenase (ADH3)

Association of Alcohol Dehydrogenase Genes with Alcohol-Related Phenotypes in a Native American Community Sample

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