Alcohol Metabolism in Human Cells Causes DNA Damage and Activates the Fanconi Anemia–Breast Cancer Susceptibility (FA-BRCA) DNA Damage Response Network
Article first published online: 15 SEP 2011
Copyright © 2011 by the Research Society on Alcoholism
Alcoholism: Clinical and Experimental Research
Volume 35, Issue 12, pages 2113–2120, December 2011
How to Cite
Abraham, J., Balbo, S., Crabb, D. and Brooks, P. J. (2011), Alcohol Metabolism in Human Cells Causes DNA Damage and Activates the Fanconi Anemia–Breast Cancer Susceptibility (FA-BRCA) DNA Damage Response Network. Alcoholism: Clinical and Experimental Research, 35: 2113–2120. doi: 10.1111/j.1530-0277.2011.01563.x
- Issue published online: 18 NOV 2011
- Article first published online: 15 SEP 2011
- Received for publication June 22, 2010; accepted March 21, 2011.
- DNA Adducts;
- Alcohol Dehydrogenase;
- Hepatocellular Carcinoma;
- Breast Cancer;
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 N2-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.