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Alcohol Clin Exp Res. 2011 Dec;35(12):2113-20. doi: 10.1111/j.1530-0277.2011.01563.x. Epub 2011 Sep 15.

Alcohol metabolism in human cells causes DNA damage and activates the Fanconi anemia-breast cancer susceptibility (FA-BRCA) DNA damage response network.

Author information

1
Section on Molecular Neurobiology, Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Rockville, Maryland, USA.

Abstract

BACKGROUND:

We recently reported that exposure of human cells in vitro to acetaldehyde resulted in the activation of the Fanconi anemia-breast cancer susceptibility (FA-BRCA) DNA damage response network.

METHODS:

To determine whether intracellular generation of acetaldehyde from ethanol metabolism can cause DNA damage and activate the FA-BRCA network, we engineered HeLa cells to metabolize alcohol by expression of human alcohol dehydrogenase (ADH) 1B.

RESULTS:

Incubation of HeLa-ADH1B cells with ethanol (20 mM) resulted in acetaldehyde accumulation in the media, which was prevented by co-incubation with 4-methyl pyrazole (4-MP), a specific inhibitor of ADH. Ethanol treatment of HeLa-ADH1B cells produced a 4-fold increase in the acetaldehyde-DNA adduct and N(2)-ethylidene-dGuo and also resulted in the activation of the FA-BRCA DNA damage response network, as indicated by a monoubiquitination of FANCD2 and phosphorylation of BRCA1. Ser 1524 was identified as 1 site of BRCA1 phosphorylation. The increased levels of DNA adducts, FANCD2 monoubiquitination, and BRCA1 phosphorylation were all blocked by 4-MP, indicating that acetaldehyde, rather than ethanol itself, was responsible for all 3 responses. Importantly, the ethanol concentration we used is within the range that can be attained in the human body during social drinking.

CONCLUSIONS:

Our results indicate that intracellular metabolism of ethanol to acetaldehyde results in DNA damage, which activates the FA-BRCA DNA damage response network.

PMID:
21919919
PMCID:
PMC3221806
DOI:
10.1111/j.1530-0277.2011.01563.x
[Indexed for MEDLINE]
Free PMC Article
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