Alcohol metabolism and epigenetics changes.

Schematic representation of DNA methylation, which converts cytosine to 5′methyl-cytosine via the actions of DNA methyltransferase (DNMT). DNA methylation typically occurs at cytosines that are followed by a guanine (i.e., CpG motifs).NOTES: SAM = S-adenosylmethionine; SAH = S-adenosylhomocysteine.

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.

Alcohol metabolism and histone acetylation. Acetyl-coenzyme A (acetyl-CoA) synthetase (AceCS), an enzyme that converts acetate to acetyl-CoA, is activated by SIRT1. Acetyl-CoA is used by histone acetyltransferase (HAT) to acetylate the lysine residues in histone proteins. This neutralizes the positive charge and allows the chromatin to assume an open conformation, thus resulting in gene activation. SIRT1 also deaceytlates acetylated histones, resulting in gene silencing. Thus, SIRT1 is a sensor that balances gene activation and silencing in the cell based on the cell’s energy status. Alcohol metabolism results in acetate formation, which is used in extrahepatic tissues to produce acetyl-CoA.NOTES: AceCS1 = Acetyl-CoA synthase 1; ADH = alcohol dehydrogenase; ALDH = Aldehyde dehydrogenase.

Oxidative pathways of alcohol metabolism. Alcohol is metabolized mainly in the cytosol by alcohol dehydrogenase (ADH) to produce acetaldehyde. At high levels of alcohol consumption, an enzyme in the endoplasmic reticulum, cytochrome P450 IIE1 (CYP2E1), becomes involved in metabolizing alcohol to acetaldehyde; this enzyme also is induced by chronic drinking. A catalase-mediated reaction in the peroxisomes is considered a minor metabolic pathway of alcohol metabolism. Acetaldehyde is further metabolized to acetate in the mitochondria. Alcohol metabolism results in the formation of NADH and thus changes the redox state of hepatocytes (i.e., increases the ratio of NADH/NAD+). Both alcohol metabolism by CYP2E1 and the re-oxidation of NADH via the electron transport chain in the mitochondria results in the formation of reactive oxygen species (ROS).

Interactions between alcohol metabolism and epigenetic mechanisms. Chronic alcohol consumption leads to lower-than-normal methylation (i.e., hypomethylation) by decreasing the levels of S-adenosylmethionine (SAM), which is used by DNA methyltransferases (DNMTs) and histone methyl transferases (HMTs) to methylate DNA and histones, respectively. Furthermore, alcohol metabolism increases the ratio of the reduced nicotinamide adenine dinucleotide (NADH) to the oxidized nicotinamide adenine dinucleotide (NAD+); this inhibits SIRT1, thereby interfering with normal histone acetylation patterns.NOTES: ATP = Adenosine triphosphate; AMPK = AMP-activated protein kinase; HAT = histone acetyl transferase; TCA = tricarboxylic acid cycle.