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Alcohol metabolism and epigenetics changes.

Zakhari S - Alcohol Res (2013)

Bottom Line: For example, the activities of enzymes involved in epigenetic modifications such as DNA and histone methylation and histone acetylation, are influenced by the levels of metabolites such as nicotinamide adenine dinucleotide (NAD), adenosine triphosphate (ATP), and S-adenosylmethionine (SAM).Chronic alcohol consumption leads to significant reductions in SAM levels, thereby contributing to DNA hypomethylation.Similarly, ethanol metabolism alters the ratio of NAD+ to reduced NAD (NADH) and promotes the formation of reactive oxygen species and acetate, all of which impact epigenetic regulatory mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Division of Metabolism and Health Effects, National Institute on Alcohol Abuse and Alcoholism, USA.

ABSTRACT
Metabolites, including those generated during ethanol metabolism, can impact disease states by binding to transcription factors and/or modifying chromatin structure, thereby altering gene expression patterns. For example, the activities of enzymes involved in epigenetic modifications such as DNA and histone methylation and histone acetylation, are influenced by the levels of metabolites such as nicotinamide adenine dinucleotide (NAD), adenosine triphosphate (ATP), and S-adenosylmethionine (SAM). Chronic alcohol consumption leads to significant reductions in SAM levels, thereby contributing to DNA hypomethylation. Similarly, ethanol metabolism alters the ratio of NAD+ to reduced NAD (NADH) and promotes the formation of reactive oxygen species and acetate, all of which impact epigenetic regulatory mechanisms. In addition to altered carbohydrate metabolism, induction of cell death, and changes in mitochondrial permeability transition, these metabolism-related changes can lead to modulation of epigenetic regulation of gene expression. Understanding the nature of these epigenetic changes will help researchers design novel medications to treat or at least ameliorate alcohol-induced organ damage.

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Related in: MedlinePlus

Alcohol’s effects on homocysteine/methionine metabolism and DNA methylation. Methionine, which is formed by methylation of homocysteine (using either 5-methyl tetrahydrofolate [5-methyl THF] or betaine as methyl donors), is essential for the production of S-adenosylmethionine (SAM), which in turn is used to methylate DNA. Chronic heavy drinking reduces folate levels and inhibits methionine synthase (MS), resulting in the reduction of methionine and SAM and the concurrent increase in homocysteine and S-adenosylhomocysteine (SAH). SAH further inhibits DNA methyltransferases (DNMTs), ultimately resulting in global hypomethylation of DNA.NOTES: MTHFR = methylene tetrahydrofolate reductase; MAT = methionine adenosyltransferase; HCC = hepatocellular carcinoma; BHMT = betaine homocysteine methyltransferases; GSH = glutathione; ATP = adenosine triphosphate; Pi = inorganic phosphate.
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f2-arcr-35-1-6: Alcohol’s effects on homocysteine/methionine metabolism and DNA methylation. Methionine, which is formed by methylation of homocysteine (using either 5-methyl tetrahydrofolate [5-methyl THF] or betaine as methyl donors), is essential for the production of S-adenosylmethionine (SAM), which in turn is used to methylate DNA. Chronic heavy drinking reduces folate levels and inhibits methionine synthase (MS), resulting in the reduction of methionine and SAM and the concurrent increase in homocysteine and S-adenosylhomocysteine (SAH). SAH further inhibits DNA methyltransferases (DNMTs), ultimately resulting in global hypomethylation of DNA.NOTES: MTHFR = methylene tetrahydrofolate reductase; MAT = methionine adenosyltransferase; HCC = hepatocellular carcinoma; BHMT = betaine homocysteine methyltransferases; GSH = glutathione; ATP = adenosine triphosphate; Pi = inorganic phosphate.

Mentions: SAM, a methyl donor for reactions catalyzed by DNMT, is generated by adding ATP to methionine by the enzyme methionine adenosyl transferase (MAT) (figure 2). After the methyl transfer reaction, SAM forms a byproduct, S-adenosyl homocysteine (SAH), which acts as a potent inhibitor of DNMT and HMTs. SAH then is broken down by SAH hydrolase (SAHH) to form homocysteine, which can either enter a set of reactions called the transsulfuration pathway to form glutathione (GSH) or be remethylated to form methionine (Grillo and Colombatto 2008). For remethylation of homocysteine, a methyl group can be transferred either from N5-methyl tetrahydrofolate (THF) by methionine synthase, or from betaine by betaine homocysteine methyl transferase (BHMT). Excessive ROS formation, which can occur during ethanol metabolism, acutely can deplete GSH. This could promote the transsulfuration of homocysteine to generate new GSH and thus divert the reactions from producing methionine and SAM, thereby decreasing DNA methylation.


Alcohol metabolism and epigenetics changes.

Zakhari S - Alcohol Res (2013)

Alcohol’s effects on homocysteine/methionine metabolism and DNA methylation. Methionine, which is formed by methylation of homocysteine (using either 5-methyl tetrahydrofolate [5-methyl THF] or betaine as methyl donors), is essential for the production of S-adenosylmethionine (SAM), which in turn is used to methylate DNA. Chronic heavy drinking reduces folate levels and inhibits methionine synthase (MS), resulting in the reduction of methionine and SAM and the concurrent increase in homocysteine and S-adenosylhomocysteine (SAH). SAH further inhibits DNA methyltransferases (DNMTs), ultimately resulting in global hypomethylation of DNA.NOTES: MTHFR = methylene tetrahydrofolate reductase; MAT = methionine adenosyltransferase; HCC = hepatocellular carcinoma; BHMT = betaine homocysteine methyltransferases; GSH = glutathione; ATP = adenosine triphosphate; Pi = inorganic phosphate.
© Copyright Policy - public-domain
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3860421&req=5

f2-arcr-35-1-6: Alcohol’s effects on homocysteine/methionine metabolism and DNA methylation. Methionine, which is formed by methylation of homocysteine (using either 5-methyl tetrahydrofolate [5-methyl THF] or betaine as methyl donors), is essential for the production of S-adenosylmethionine (SAM), which in turn is used to methylate DNA. Chronic heavy drinking reduces folate levels and inhibits methionine synthase (MS), resulting in the reduction of methionine and SAM and the concurrent increase in homocysteine and S-adenosylhomocysteine (SAH). SAH further inhibits DNA methyltransferases (DNMTs), ultimately resulting in global hypomethylation of DNA.NOTES: MTHFR = methylene tetrahydrofolate reductase; MAT = methionine adenosyltransferase; HCC = hepatocellular carcinoma; BHMT = betaine homocysteine methyltransferases; GSH = glutathione; ATP = adenosine triphosphate; Pi = inorganic phosphate.
Mentions: SAM, a methyl donor for reactions catalyzed by DNMT, is generated by adding ATP to methionine by the enzyme methionine adenosyl transferase (MAT) (figure 2). After the methyl transfer reaction, SAM forms a byproduct, S-adenosyl homocysteine (SAH), which acts as a potent inhibitor of DNMT and HMTs. SAH then is broken down by SAH hydrolase (SAHH) to form homocysteine, which can either enter a set of reactions called the transsulfuration pathway to form glutathione (GSH) or be remethylated to form methionine (Grillo and Colombatto 2008). For remethylation of homocysteine, a methyl group can be transferred either from N5-methyl tetrahydrofolate (THF) by methionine synthase, or from betaine by betaine homocysteine methyl transferase (BHMT). Excessive ROS formation, which can occur during ethanol metabolism, acutely can deplete GSH. This could promote the transsulfuration of homocysteine to generate new GSH and thus divert the reactions from producing methionine and SAM, thereby decreasing DNA methylation.

Bottom Line: For example, the activities of enzymes involved in epigenetic modifications such as DNA and histone methylation and histone acetylation, are influenced by the levels of metabolites such as nicotinamide adenine dinucleotide (NAD), adenosine triphosphate (ATP), and S-adenosylmethionine (SAM).Chronic alcohol consumption leads to significant reductions in SAM levels, thereby contributing to DNA hypomethylation.Similarly, ethanol metabolism alters the ratio of NAD+ to reduced NAD (NADH) and promotes the formation of reactive oxygen species and acetate, all of which impact epigenetic regulatory mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Division of Metabolism and Health Effects, National Institute on Alcohol Abuse and Alcoholism, USA.

ABSTRACT
Metabolites, including those generated during ethanol metabolism, can impact disease states by binding to transcription factors and/or modifying chromatin structure, thereby altering gene expression patterns. For example, the activities of enzymes involved in epigenetic modifications such as DNA and histone methylation and histone acetylation, are influenced by the levels of metabolites such as nicotinamide adenine dinucleotide (NAD), adenosine triphosphate (ATP), and S-adenosylmethionine (SAM). Chronic alcohol consumption leads to significant reductions in SAM levels, thereby contributing to DNA hypomethylation. Similarly, ethanol metabolism alters the ratio of NAD+ to reduced NAD (NADH) and promotes the formation of reactive oxygen species and acetate, all of which impact epigenetic regulatory mechanisms. In addition to altered carbohydrate metabolism, induction of cell death, and changes in mitochondrial permeability transition, these metabolism-related changes can lead to modulation of epigenetic regulation of gene expression. Understanding the nature of these epigenetic changes will help researchers design novel medications to treat or at least ameliorate alcohol-induced organ damage.

Show MeSH
Related in: MedlinePlus