Clastogenic factors in the plasma of patients with hepatitis C: their possible role at the origin of hepatocarcinoma

Abstract

Clastogenic factors (CF) are endogenous clastogens composed of lipid peroxidation products, cytokines, and abnormal nucleotides of inosine. They are regularly observed after radiation exposure and in chronic inflammatory diseases, where they are supposed to be risk factors for carcinogenesis. In the present study, we evaluate clastogenic activity in the plasma of patients with chronic hepatitis C, HCV-positive liver cirrhosis, and hepatocarcinoma in comparison to liver metastasis. Plasma ultrafiltrates from patients were added to blood cultures of healthy donors (CF test). The chromosomal aberration rates observed in 100 metaphases after 48 hours of cultivation were expressed as adjusted clastogenic scores (ACS). The differences in ACS between the four patient groups and controls were highly significant and represented a 10-fold increase in chromatid-type aberrations. The ACS of patients with cirrhosis and hepatocarcinoma were higher than those of hepatitis patients without these complications, but the differences did not reach statistical significance. Because of cytotoxic effects, the cultures did not grow for 10/17 patients with hepatocarcinoma and were repeated with a reduced volume of ultrafiltrate (0.1 instead of 0.25 mL). The ACS were highest in these 10 patients. When the CF activity of HCV-positive hepatocarcinoma was compared to metastasis because of other malignancies, the differences in ACS were highly significant for the cultures set up with the reduced quantity of ultrafiltrate. The percentage of CF-positive samples was 100% for hepatocarcinoma and 9% for metastasis. The results show that the chromosome-damaging effects of CF increase as the disease progresses to cirrhosis and liver cancer. Formed via the intermediacy of superoxide and generating more superoxide, CF are responsible for an autosustained, long-lived DNA-damaging process, which is documented at the chromosomal level by our technique.