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,N(6)-ethenodeoxyadenosine (epsilon dA) in human liver samples obtained from a group of patients diagnosed with
hepatitis,
fatty liver,
fibrosis and
cirrhosis,
primary hemochromatosis and
Wilson's disease. Using an immunohistochemical method, the relative mean pixel intensity of randomly selected nuclei was measured by imaging software; positively stained cell nuclei (arbitrary mean pixel intensity > or =0.5) were counted. Prevalence of epsilon dA (%) was calculated from the ratio of a number of positively stained cell nuclei over a total number of cells counted. When compared with normal livers (3.1%), the percent 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 percent prevalence in alcohol
fibrosis was as high as in the liver from
Wilson's disease (50.7%) and
hemochromatosis (33%) patients. This is the first demonstration of increased epsilon dA 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 probably 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.