DNA damage and neurotoxicity of chronic alcohol abuse - PubMed (original) (raw)

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DNA damage and neurotoxicity of chronic alcohol abuse

Inna I Kruman et al. Exp Biol Med (Maywood). 2012 Jul.

Abstract

Chronic alcohol abuse results in a variety of pathological effects including damage to the brain. The causes of alcohol-induced brain pathology are presently unclear. Several mechanisms of pathogenicity of chronic alcoholism have been proposed, including accumulation of DNA damage in the absence of repair, resulting in genomic instability and death of neurons. Genomic instability is a unified genetic mechanism leading to a variety of neurodegenerative disorders. Ethanol also likely interacts with various metabolic pathways, including one-carbon metabolism (OCM). OCM is critical for the synthesis of DNA precursors, essential for DNA repair, and as a methyl donor for various methylation events, including DNA methylation. Both DNA repair and DNA methylation are critical for maintaining genomic stability. In this review, we outline the role of DNA damage and DNA repair dysfunction in chronic alcohol-induced neurodegeneration.

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Figures

Figure 1

Figure 1

How alcohol may impact DNA. Ethanol is metabolized to acetaldehyde (AA) by alcohol dehydrogenase (ADH), cytochrome P450 2E1 (CYP2E1) and catalase. AA is metabolized to acetate by aldehyde dehydrogenase 2 (ALDH2). Catalase and CYP2E1 are particularly relevant to ethanol metabolism in brain tissue. The CYP2E1-dependent pathway is a major contributor to ethanol-generated reactive oxygen species (ROS). ROS induce DNA damage

Figure 2

Figure 2

One-carbon metabolism as a target for ethanol. BHMT, betaine-homocysteine methyltransferase; CBS, cystathionine _β_-synthase; DHF, dihydrofolate; dNTP, deoxyribonucleotide triphosphate; dTMP, deoxythymidine monophosphate; dUMP, deoxyuridine monophosphate; GARFT, glycinamide ribonucleotide formyltransferase; Hcy, homocysteine; MS, methionine synthase; MTHFR, methylene THF reductase; SAH, _S_-adenosyl homocysteine; SHMT, serine hydroxy-methyltransferase; THF, tetrahydrofolate; TS, thymidylate synthase

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