Figure 2.
Effect of CYP2E1- and acetaldehyde-mediated generation of reactive oxygen species (ROS)/reactive nitrogen species (RNS) and DNA adducts on DNA damage. Induced expression of CYP2E1 results in the oxidation of ethanol, and the formation of acetaldehyde and reactive species (ROS/RNS). Acetaldehyde inhibits DNA repair mechanism and anti-oxidative defense system (AODS) [5]. Acetaldehyde and inflammation-derived cytokines activate nuclear factor kappa-B (NF-κB) in colon cells [31]. NF-κB stimulates the expression of cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS), which promote the additional formation of ROS, RNS, and lipid peroxidation products, such trans-4-hydroxy-2-nonenal (4HNE) and malondialdehyde (MDA), that interact with DNA bases to form adducts [16,24]. N-hydroxyethyl (HE) radicals and acetaldehyde (AA) adducts are formed during ethanol metabolism. Pyrimido-[1,2-a] purin-10(3H)-one (M1G) and MDA-acetaldehyde (MAA) adducts are generated by the reaction of DNA and protein with MDA [16,24]. Additional adducts are formed by the reaction of DNA with 4HNE. DNA adducts formed as a result of MDA and 4HNE are marked as in a rectangle. The generated DNA and protein adducts may react with DNA bases to form etheno-DNA adducts, which can promote DNA damage [5]. DNA repair mechanism refers to O6-guanine-methyltransferase and 8-oxo-guanine-DNA-glycosylateis, which are both inhibited by AA and nitric oxide (NO) [5]. Ethanol produces a nitric oxide system (iNOS) that generates NO [5]. Figure adapted from [16].