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Carcinogenesis Advance Access published online on January 23, 2004
Carcinogenesis, doi:10.1093/carcin/bgh089
© 2004 by Oxford University Press
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© 2004 Oxford University Press

CARCINOGENESIS

Immunohistochemical detection of 1,N6-ethenodeoxadenosine in nuclei of human liver affected by diseases predisposing to hepato-carcinogenesis

Alexander Frank 1, Helmut K. Seitz 2, Helmut Bartsch 1, Norbert Frank 1, and Jagadeesan Nair 1*

1 Division of Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
2 Department of Medicine, Salem Medical Center, Zeppelinstr.11-33, 69121 Heidelberg, Germany

* Corresponding author. E-mail: j.nair{at}dkfz.de.

Received 3 September 2003 ; revised 22 December 2003 ; accepted 14 January 2004

Abstract

Increased oxidative stress and lipid peroxidation (LPO) are implicated in multistage carcinogenesis. Recent studies have shown that LPO-derived reactive hydroxyalkenals can form promutagenic exocyclic etheno-DNA adducts in vivo. Such DNA damage was found to be increased in the liver of patients with metal storage diseases and in colon adenomas of familial adenomatous polyposis patients. We now have investigated the levels of 1,N6-ethenodeoxyadenosine in human liver samples obtained from group of patients diagnosed with hepatitis, fatty liver, fibrosis and cirrhosis, primary hemochromatosis and Wilson's disease. Using a immunohistochemical method, the relative mean pixel intensity of randomly selected nuclei was measured by imaging software; positively stained cell nuclei (arbitrary mean pixel intensity >= 0.5) were counted. Prevalence of 1,N6-ethenodeoxyadenosine (%) was calculated from the ratio of number of positively stained cell nuclei over a total number of cells counted. When compared to normal livers (3.1%), the % prevalence (means) was significantly higher in specimens of alcoholic fatty liver (15%) and fibrosis patients (50%) but not in samples with hepatitis (induced by various factors) (6.2%). The % prevalence in alcohol fibrosis was as high as in liver from Wilson's disease (50.7%) and hemochromatosis (33%) patients. This is the first demonstration of increased 1,N6-ethenodeoxyadenosine in human liver diseases due to alcohol abuse. We conclude that excessive hepatic DNA damage, as assessed by miscoding etheno-DNA adduct in the nuclei of liver biopsies, is likely to be caused by alcohol induced oxidative stress and LPO. In cancer prone liver diseases (fatty liver, cirrhosis/fibrosis) such damage may act as a driving force towards malignancy.


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