Detection of carcinogenic etheno-DNA adducts in children and adolescents with non-alcoholic steatohepatitis (NASH)

Ulrike Teufel; Teresa Peccerella; Guido Engelmann; Thomas Bruckner; Christa Flechtenmacher; Gunda Millonig; Felix Stickel; Georg F Hoffmann; Peter Schirmacher; Sebastian Mueller; Helmut Bartsch; Helmut K Seitz

doi:10.3978/j.issn.2304-3881.2015.12.03

Detection of carcinogenic etheno-DNA adducts in children and adolescents with non-alcoholic steatohepatitis (NASH)

Hepatobiliary Surg Nutr. 2015 Dec;4(6):426-35. doi: 10.3978/j.issn.2304-3881.2015.12.03.

Affiliation

¹ 1 Department of Paediatrics, University of Heidelberg, Heidelberg, Germany ; 2 Alcohol Research Centre, University of Heidelberg and Department of Medicine (Gastroenterology & Hepatology), Salem Medical Centre, Heidelberg, Germany ; 3 Institute of Medical Biometry and Informatics, 4 Department of Pathology, University of Heidelberg, Heidelberg, Germany ; 5 Hepatology Unit, Clinic Beau-Site Hirslanden, Bern, Switzerland ; 6 Erstwhile: Division of Toxicology and Cancer Risk Factors, German Cancer Research Centre (DKFZ), Heidelberg, Germany.

PMID: 26734629
PMCID: PMC4689692
DOI: 10.3978/j.issn.2304-3881.2015.12.03

Abstract

Background: Carcinogenic exocyclic-DNA adducts like 1,N(6)-etheno-2'-deoxyadenosine (εdA) are formed 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 been detected in cancer prone liver diseases including alcoholic liver disease (ALD). In ALD εdA levels correlated significantly with cytochrome P-450 2E1 (CYP2E1) expression which is also induced in non-alcoholic steatohepatitis (NASH). We investigated the occurrence of εdA adducts in children with NASH as a DNA damage marker.

Methods: Liver biopsies from 21 children/adolescents with histologically proven NASH were analysed for hepatic fat content, inflammation, and fibrosis. εdA levels in DNA, CYP2E1-expression and protein bound 4-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 not elevated 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 suggest that LPO-derived etheno-adducts are implicated in NASH. Whether these adducts may serve as predictive risk 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).