The mechanisms by which chronic alcohol consumption enhances
carcinogenesis include
acetaldehyde (AA) generated by
alcohol dehydrogenase and
reactive oxygen species (ROS) generated predominantly by
cytochrome P450 2E1 (
CYP2E1), but also by other factors during
inflammation. In addition,
ethanol also alters epigenetics by changing
DNA and
histone methylation and acetylation. A loss of
retinoic acid due to a CYP2E1-related enhanced degradation results in enhanced cellular proliferation and decreased cell differentiation. Changes in cancer genes and in signaling pathways (MAPK, RAS, Rb, TGFβ, p53, PTEN, ECM,
osteopontin, Wnt) may also contribute to
ethanol-mediated mechanisms in
carcinogenesis. Finally, immunosuppression may facilitate
tumor spread. In the present review major emphasis is led on AA and ROS. While AA binds to
proteins and
DNA generating carcinogenic
DNA adducts and inhibiting DNA repair and DNA methylation, ROS results in lipid peroxidation with the generation of lipid peroxidation products such as 4-hydoxynonenal which binds to
DNA-forming highly carcinogenic exocyclic
DNA adducts. ROS production correlates significantly with
CYP2E1 in the liver but also in the esophagus, and its generation can be significantly reduced by the specific
CYP2E1 inhibitor
clomethiazole. Finally, CMZ also inhibits alcohol-mediated
nitrosamine-induced hepatocarcinogenesis.