Oxidative damage is increased in human liver tissue adjacent to hepatocellular carcinoma.
Accumulation of genetic alterations in hepatocarcinogenesis is closely associated with chronic inflammatory liver disease. 8-oxo-2'-deoxyguanosine (8-oxo-dG), the major promutagenic DNA adduct caused by reactive oxygen species (ROS), leads to G:C --> T:A transversions. These lesions can be enzymatically repaired mainly by human MutT homolog 1 (hMTH1), human 8-oxo-guanine DNA glycosylase (hOGG1) and human MutY homolog (hMYH). The aim of this study was to evaluate the extent of oxidative damage and its dependence on the cellular antioxidative capacity and the expression of specific DNA repair enzymes in tumor (tu) and corresponding adjacent nontumor (ntu) liver tissue of 23 patients with histologically confirmed hepatocellular carcinoma. 8-oxo-dG levels, as detected by high-pressure liquid chromatography with electrochemical detection, were significantly (P =.003) elevated in ntu tissue (median, 129 fmol/microg DNA) as compared to tu tissue (median, 52 fmol/microg DNA), and were closely associated with inflammatory infiltration. In ntu tissue, the hepatic iron concentration and malondialdehyde levels were significantly (P =.001) higher as compared to tu tissue. Glutathione content, glutathione peroxidase activity and manganese superoxide dismutase messenger RNA (mRNA) expression did not show statistical differences between ntu and tu tissue. Real-time reverse transcription polymerase chain reaction revealed in tu tissue significantly (P =.014) higher hMTH1 mRNA expression compared to ntu tissue. In contrast, hMYH mRNA expression was significantly (P <.05) higher in ntu tissue. No difference in hOGG1 mRNA expression was seen between tu and ntu. In conclusion, these data suggest that ROS generated by chronic inflammation contribute to human hepatocarcinogenesis. The role of DNA repair enzymes appears to be of reactive rather than causative manner.
Jüngst
Christoph
C
Department of Internal Medicine I, University of Bonn, Bonn, Germany.
Cheng
Bin
B
Gehrke
Ralph
R
Schmitz
Volker
V
Nischalke
Hans Dieter
HD
Ramakers
Jan
J
Schramel
Peter
P
Schirmacher
Peter
P
Sauerbruch
Tilman
T
Caselmann
Wolfgang Helmut
WH
D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D005260:Female; D006801:Humans; D008099:Liver / Q000737:chemistry / Q000378:metabolism*; D008113:Liver Neoplasms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000096:biosynthesis
D012333:RNA, Messenger