title: The generation of carcinogenic etheno-DNA adducts in the liver of patients with nonalcoholic fatty liver disease.
abstract: BACKGROUND
  Nonalcoholic fatty liver disease (NAFLD), in particular its more aggressive form nonalcoholic steatohepatitis (NASH) is increasingly observed as a cause of end stage liver disease and hepatocellular carcinoma (HCC). Reactive oxygen species (ROS) are an important factor in the pathogenesis of HCC. ROS can react with polyunsaturated fatty acids derived from membrane phospholipids resulting in the production of reactive aldehydes as lipid oxidation (LPO) byproducts, such as 4-hydroxynonenal (4 HNE). 4 HNE can react with DNA to form mutagenic exocyclic etheno-DNA adducts. ROS is induced by inflammatory processes, but also by induction of cytochrome P450 2E1 (CYP2E1), as seen with chronic alcohol consumption.
  
  
  METHODS
  Immunohistochemical detection of CYP2E1, 4 HNE and hepatic exocyclic etheno-DNA adducts was performed on liver sections from 39 patients with NFLD. Spearman rank correlation was calculated to examine possible correlations.
  
  
  RESULTS
  Exocyclic etheno-DNA adducts were detected and correlated significantly with 4 HNE, but not with CYP2E1.
  
  
  CONCLUSIONS
  This is the first description of highly carcinogenic exocyclic etheno-DNA adducts in NAFLD patients. We could show that exocyclic etheno-DNA adducts significantly correlated with lipid peroxidation product 4 HNE, but not with CYP2E1, implying that in NAFLD ROS generation with consecutive DNA damage is rather inflammation driven through various cytokines than by induction of CYP2E1.
authors.affiliation: 1 Centre of Alcohol Research, University of Heidelberg, Heidelberg, Germany ; 2 Department of Medicine (Gastroenterology & Hepatology), Salem Medical Centre, Heidelberg, Germany ; 3 Division of Toxicology and Cancer Risk Factors, Germany Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors.forename: Kirsten-Berit
authors.initials: KB
authors.lastname: Linhart
authors.affiliation: 1 Centre of Alcohol Research, University of Heidelberg, Heidelberg, Germany ; 2 Department of Medicine (Gastroenterology & Hepatology), Salem Medical Centre, Heidelberg, Germany ; 3 Division of Toxicology and Cancer Risk Factors, Germany Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Glassen
authors.affiliation: 1 Centre of Alcohol Research, University of Heidelberg, Heidelberg, Germany ; 2 Department of Medicine (Gastroenterology & Hepatology), Salem Medical Centre, Heidelberg, Germany ; 3 Division of Toxicology and Cancer Risk Factors, Germany Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors.forename: Teresa
authors.initials: T
authors.lastname: Peccerella
authors.affiliation: 1 Centre of Alcohol Research, University of Heidelberg, Heidelberg, Germany ; 2 Department of Medicine (Gastroenterology & Hepatology), Salem Medical Centre, Heidelberg, Germany ; 3 Division of Toxicology and Cancer Risk Factors, Germany Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Waldherr
authors.affiliation: 1 Centre of Alcohol Research, University of Heidelberg, Heidelberg, Germany ; 2 Department of Medicine (Gastroenterology & Hepatology), Salem Medical Centre, Heidelberg, Germany ; 3 Division of Toxicology and Cancer Risk Factors, Germany Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors.forename: Heinz
authors.initials: H
authors.lastname: Linhart
authors.affiliation: 1 Centre of Alcohol Research, University of Heidelberg, Heidelberg, Germany ; 2 Department of Medicine (Gastroenterology & Hepatology), Salem Medical Centre, Heidelberg, Germany ; 3 Division of Toxicology and Cancer Risk Factors, Germany Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Bartsch
authors.affiliation: 1 Centre of Alcohol Research, University of Heidelberg, Heidelberg, Germany ; 2 Department of Medicine (Gastroenterology & Hepatology), Salem Medical Centre, Heidelberg, Germany ; 3 Division of Toxicology and Cancer Risk Factors, Germany Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors.forename: Helmut K
authors.initials: HK
authors.lastname: Seitz
keywords: Nonalcoholic fatty liver disease (NAFLD); etheno-DNA adducts; hepatocellular carcinoma (HCC)