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Review
. 2014:3:56-62.
doi: 10.1016/j.redox.2014.08.009. Epub 2014 Sep 6.

The role of reactive oxygen species (ROS) and cytochrome P-450 2E1 in the generation of carcinogenic etheno-DNA adducts

Kirsten Linhart  1 , Helmut Bartsch  2 , Helmut K Seitz  3
Affiliations
Review

The role of reactive oxygen species (ROS) and cytochrome P-450 2E1 in the generation of carcinogenic etheno-DNA adducts

Kirsten Linhart et al. Redox Biol. 2014.

Abstract

Exocyclic etheno-DNA adducts are mutagenic and carcinogenic and are formed by the reaction of lipidperoxidation (LPO) products such as 4-hydoxynonenal or malondialdehyde with DNA bases. LPO products are generated either via inflammation driven oxidative stress or via the induction of cytochrome P-450 2E1 (CYP2E1). In the liver CYP2E1 is induced by various compounds including free fatty acids, acetone and ethanol. Increased levels of CYP2E1 and thus, oxidative stress are observed in the liver of patients with non-alcoholic steatohepatitis (NASH) as well as in the chronic alcoholic. In addition, chronic ethanol ingestion also increases CYP2E1 in the mucosa of the oesophagus and colon. In all these tissues CYP2E1 correlates significantly with the levels of carcinogenic etheno-DNA adducts. In contrast, in patients with non-alcoholic steatohepatitis (NASH) hepatic etheno-DNA adducts do not correlate with CYP2E1 indicating that in NASH etheno-DNA adducts formation is predominately driven by inflammation rather than by CYP2E1 induction. Since etheno-DNA adducts are strong mutagens producing various types of base pair substitution mutations as well as other types of genetic damage, it is strongly believed that they are involved in ethanol mediated carcinogenesis primarily driven by the induction of CYP2E1.

Keywords: Carcinogenesis; Cytochrome P450-2E1; Ethanol; Etheno-DNA adducts; Lipidperoxidation products; Non-alcoholic fatty liver disease.

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Figures

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Graphical abstract
Fig. 1
Fig. 1
Simplified pathophysiology of reactive oxygen species (ROS) and etheno-DNA adduct formation. Inflammation driven cytokine secretion results among others in NFκB activation and in the activation of NADPH oxidase (NADPH-Ox) as well as myeloperoxidase (MPO). NFκB is also activated by acetaldehyde, the first metabolite of ethanol oxidation. NFκB stimulates lipoxigenase (LOX), cyclooxygenase 2 (COX2), and inducible nitric oxide synthase (iNOS). As a result ROS and reactive nitrogen species (RNS) are generated, which lead to lipidperoxidation with the occurrence of lipidperoxidation products such as 4-hydroxynonenal (4-HNE), 4-hydroxyhydroperoxy-2-nonenal (HPNE), and malondialdehyde (MDA). These adducts react with DNA bases to form exocyclic etheno/propane-DNA adducts. Chronic alcohol consumption results in the induction of cytochrome P-4502 E1 which is involved in ethanol oxidation through the microsomal ethanol oxidizing pathway. During this reaction ROS is generated without inflammation. Other compounds such as free fatty acids or acetone also induce CYP2E1 which is especially relevant in nonalcoholic fatty liver disease (NAFLD), when the liver is loaded with fat and in patients with diabetes mellitus when acetone is generated in the liver.
Fig. 2
Fig. 2
Generation of various etheno DNA-adducts. Deoxyadenine, deoxycytosine, and deoxyguanosine react with lipidperoxidation products to form 1N6-ethano-2′-deoxyadenosine (εdA), 3,N4-etheno-2′-deoxycytidine (εdC), and 1,N2-etheno-2′-deoxyguanosine (1,N2εdG), N2,3-etheno-2′-deoxyguanosine (N2,3-εdG), and HNE-derived 1,N2-propano-2′-deoxyguanosine adduct (HNE-dG).
Fig. 3
Fig. 3
Immunohistology of εdA in two liver biopsies from patients with alcoholic liver disease (A) and control patients with a normal liver (B). The brownish colour shows εdA. This adduct occurs in the nuclei of the hepatocytes and the percentage of nuclei positive hepatocytes can be counted. A significant load of etheno adducts is observed in ALD, while the control healthy liver reveals background activity only.
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