Interferon reduces somatic mutation of mitochondrial DNA in liver tissues from chronic viral hepatitis patients.
We recently reported that the genetic instability resulting in the high rate of mitochondrial DNA (mtDNA) mutation in noncancerous liver tissue is consistent with the multicentric hepatocarcinogenesis detected clinically. Interferon (IFN) has been reported to reduce hepatocarcinogenesis in individuals with hepatitis virus infection. Liver biopsy specimens were obtained from 26 patients with chronic hepatitis C virus (HCV) infection before and after IFN therapy (total dose: 252 million units). The mean (+/-SD) age of the study population was 45 +/- 9 years and 13 (50%) were male [mode of acquisition: blood transfusion (27%), unknown (73%); viral load: 5.2 +/- 1.1 k copies/mL; duration of infection: 17 +/- 9 years (65%), unknown (35%); genotype: I (4%), II (80%), III (8%), IV (8%); alcohol intake: positive (31%), negative (69%)]. DNA samples were extracted from the specimens and subjected to direct sequencing. The mtDNA mutation frequency in the D-loop was increased in liver specimens from individuals with HCV infection compared with 21 controls (2.5 vs 0.6, P < 0.001). IFN therapy decreased the mtDNA mutation (mean difference = 0.7, P < 0.001) and the decreased number of mtDNA mutations was positively correlated with suppression of the total histological activity index score (mean difference = 1.3, P < 0.01). These results clearly indicate that the mutational rate of mtDNA is strongly associated with IFN therapy. Thus, analysis of mtDNA could provide a new criterion for the therapeutic evaluation of the effect of IFN, and may be useful for the prediction of risk of carcinogenesis.
Nishikawa
M
M
Biochemistry & Molecular Pathology, Osaka City University Medical School, Osaka, Japan. nishikawa@med.osaka-cu.ac.jp
Nishiguchi
S
S
Kioka
K
K
Tamori
A
A
Inoue
M
M
D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000517:prevention & control; D004272:DNA, Mitochondrial / Q000187:drug effects* / Q000235:genetics; D005260:Female; D019694:Hepatitis B, Chronic / Q000150:complications / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000150:complications / Q000235:genetics; D006801:Humans; D007372:Interferons / Q000494:pharmacology* / Q000627:therapeutic use; D008113:Liver Neoplasms / Q000209:etiology / Q000517:prevention & control; D008297:Male; D009154:Mutation; D016133:Polymerase Chain Reaction; D012367:RNA, Viral / Q000097:blood
D000998:Antiviral Agents; D004272:DNA, Mitochondrial; D012367:RNA, Viral; D007372:Interferons