Efficiency of early intervention by N-acetyl cysteine on liver fibrosis and markers of hepatocellular carcinogenesis induced by diethylnitrosamine in mice

Background N-acetylcysteine is a hepatoprotective agent with antioxidant and therapeutic potential. In this study, the effectiveness of early and late intervention with NAC in hepatocellular carcinogenesis (HCC) induced by diethyl nitrosamine (DEN) in mice has been evaluated. Methods Newborn mice (14-day-old) were divided into 4 groups (n = 4/group). Control, HCC group, early NAC intervention, and late NAC intervention group. NAC treatments were followed after HCC induction by DEN administration (50 mg/kg, i.p), followed by phenobarbitone (PB, 500 mg/L via drinking water). In the early intervention group, NAC (150 mg/kg) was given by gavage during 8–16 weeks after birth. In the late group intervention, NAC was given during 16–24 weeks of birth. After 7 months (28 weeks), mice were sacrificed; blood and liver tissues were collected. Liver damage markers, as well as serum levels of liver fibrosis biomarker, PIIINP (N-terminal propeptide type III collagen), and antioxidant capacity (TAC) were determined. Histology examination on liver biopsies, together with changes in tissue total oxidant factors and liver cells proliferation index (Ki67) were determined in liver tissues. Results Early intervention with NAC in mice during HCC induction resulted in a significant decrease in serum levels of liver damage markers, AST and ALT. This finding was corroborated with liver histology data, particularly tissue fibrosis. Intervention with NAC during HCC progression resulted in a significant decrease in serum PIIINP and hepatic total oxidative stress, GSH, and KI67 expression. NAC treatment also resulted in TAC overregulation. Conclusion Early treatment with NAC in HCC model of mice can improve liver fibrosis and cancer through antioxidant system. However, NAC intervention at later stages of HCC development encounters multiple molecular and cellular pathways with less therapeutic efficiency. Hence, treatment with NAC at the early stages of HCC, where oxidative stress is seriously disturbed, is beneficial in the prevention of tumor development. NAC intervention at early stage of HCC induction in mice greatly subsided HCC-related liver damage markers, along with liver fibrosis and cancer cell proliferation. This data suggests that NAC can efficiently delay and ameliorate tissue fibrosis and cancer promotion.