Author/Authors :
teufel, ulrike university of heidelberg - department of paediatrics, Heidelberg, Germany , peccerella, teresa university of heidelberg - alcohol research centre, salem medical centre - department of medicine (gastroenterology hepatology), Heidelberg, Germany , engelmann, guido university of heidelberg - department of paediatrics, Heidelberg, Germany , bruckner, thomas institute of medical biometry and informatics, Germany , flechtenmacher, christa university of heidelberg - department of pathology, Heidelberg, Germany , millonig, gunda university of heidelberg - alcohol research centre, salem medical centre - department of medicine (gastroenterology hepatology), Heidelberg, Germany , stickel, felix clinic beau-site hirslanden, hepatology unit, Bern, Switzerland , hoffmann, georg f. university of heidelberg - department of paediatrics, Heidelberg, Germany , schirmacher, peter university of heidelberg - department of pathology, Heidelberg, Germany , mueller, sebastian university of heidelberg - alcohol research centre, salem medical centre, - department of medicine (gastroenterology hepatology), Heidelberg, Germany , bartsch, helmut german cancer research centre (dkfz) - division of toxicology and cancer risk factors, Heidelberg, Germany , seitz, helmut k. university of heidelberg - centre of alcohol research, salem medical centre - department of medicine (gastroenterology hepatology), Heidelberg, Germany
Abstract :
Background: Carcinogenic exocyclic-DNA adducts like 1,N6-etheno-2 -deoxyadenosine (εdA) areformed through reactive intermediates of 4-hydroxynonenal (4-HNE) or other lipid peroxidation (LPO)products with the DNA bases A, C, methyl-C and G. High levels of hepatic etheno-DNA adducts have beendetected in cancer prone liver diseases including alcoholic liver disease (ALD). In ALD εdA levels correlatedsignificantly with cytochrome P-450 2E1 (CYP2E1) expression which is also induced in non-alcoholicsteatohepatitis (NASH). We investigated the occurrence of εdA adducts in children with NASH as a DNAdamage marker.Methods: Liver biopsies from 21 children/adolescents with histologically proven NASH were analysed forhepatic fat content, inflammation, and fibrosis. εdA levels in DNA, CYP2E1-expression and protein bound4-hydroxynonenal (HNE) were semi-quantitatively evaluated by immunohistochemistry.Results: Among 21 NASH children, εdA levels in the liver were high in 3, moderate in 5, weak in 9 and notelevated in 4 patients. There was a positive correlation between CYP2E1 and protein-bound 4-HNE (r=0.60;P=0.008) and a trend for a positive relationship for CYP2E1 vs. staining intensity of εdA (r=0.45; P=0.06).Inflammatory activity and fibrosis correlated significantly (r=0.49, P=0.023).Conclusions: Our results demonstrate for the first time the presence of elevated carcinogenic etheno-DNA lesions (εdA) in the majority (17/21) of liver biopsies from young NASH patients. Our data suggestthat LPO-derived etheno-adducts are implicated in NASH. Whether these adducts may serve as predictiverisk markers in NASH children to develop hepatocellular cancer later in life remains to be investigated.
Keywords :
Cytochrome P , 450 2E , etheno , DNA adducts , hepatocellular cancer , lipidperoxidation , induced DNA damage , non , alcoholic steatohepatitis in children (NASH in children)
