Hepatic oxidative DNA damage correlates with iron overload in chronic hepatitis C patients.
Hepatic oxidative stress occurs in chronic hepatitis C (CH-C), but little is known about its producing mechanisms and precise role in the pathogenesis of the disease. To determine the relevance of hepatic oxidatively generated DNA damage in CH-C, 8-hydroxy-2'-deoxyguanosine (8-OHdG) adducts were quantified in liver biopsy specimens by immunohistochemical staining, and its relationship with clinical, biochemical, and histological parameters, and treatment response was assessed in 40 CH-C patients. Hepatic 8-OHdG counts were significantly correlated with serum transaminase levels (r=0.560, p=0.0005) and histological grading activity (p=0.0013). Remarkably, 8-OHdG levels were also significantly related to body and hepatic iron storage markers (vs serum ferritin, r=0.565, p=0.0004; vs hepatic total iron score, r=0.403, p=0.0119; vs hepatic hepcidin messenger RNA, r=0.516, p=0.0013). Baseline hepatic oxidative stress was more prominent in nonsustained virological responder (non-SVR) than in SVR to interferon (IFN)/ribavirin treatment (50.8 vs 32.7 cells/10(5) microm2, p=0.0086). After phlebotomy, hepatic 8-OHdG levels were significantly reduced from 53.4 to 21.1 cells/10(5) microm2 (p=0.0125) with concomitant reductions of serum transaminase and iron-related markers in CH-C patients. In conclusion, this study showed that hepatic oxidatively generated DNA damage frequently occurs and is strongly associated with increased iron deposition and hepatic inflammation in CH-C patients, suggesting that iron overload is an important mediator of hepatic oxidative stress and disease progression in chronic HCV infection.
Fujita
Naoki
N
Department of Gastroenterology and Hepatology, Division of Clinical Medicine and Biomedical Science, Institute of Medical Science, Mie University Graduate School of Medicine, Mie, Japan. nfujita@clin.medic.mie-u.ac.jp
Horiike
Shinichiro
S
Sugimoto
Ryosuke
R
Tanaka
Hideaki
H
Iwasa
Motoh
M
Kobayashi
Yoshinao
Y
Hasegawa
Koji
K
Ma
Ning
N
Kawanishi
Shosuke
S
Adachi
Yukihiko
Y
Kaito
Masahiko
M
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D023181:Antimicrobial Cationic Peptides / Q000097:blood; D000998:Antiviral Agents / Q000627:therapeutic use; D001219:Aspartate Aminotransferases / Q000097:blood; D018736:DNA Adducts / Q000378:metabolism*; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D004359:Drug Therapy, Combination; D005260:Female; D005293:Ferritins / Q000097:blood; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000378:metabolism*; D064451:Hepcidins; D006801:Humans; D007372:Interferons / Q000627:therapeutic use; D019190:Iron Overload / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D012254:Ribavirin / Q000627:therapeutic use
D023181:Antimicrobial Cationic Peptides; D000998:Antiviral Agents; D018736:DNA Adducts; C578702:HAMP protein, human; D064451:Hepcidins; D012254:Ribavirin; D000080242:8-Hydroxy-2'-Deoxyguanosine; D005293:Ferritins; D007372:Interferons; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D003849:Deoxyguanosine