Effect of berberine on hepatocyte proliferation, inducible nitric oxide synthase expression, cytochrome P450 2E1 and 1A2 activities in diethylnitrosamine- and phenobarbital-treated rats

This study investigated the effect of berberine on the early phase of hepatocarcinogenesis stimulated by diethylnitrosamine (DEN, 150 mg/kg, 4 weeks) plus phenobarbital (PB, 75 mg/kg, 7 days) in rats. The expressions of proliferating cell nuclear antigen (PCNA) and inducible nitric oxide synthase (iNOS) were evaluated by immunohistochemistry. The activities of CYP isoenzymes were analyzed using different probe drugs including chlorzoxazone (CYP2E1) and phenacetin (CYP1A2) by high-performance liquid chromatography (HPLC) in vivo or in vitro. Results showed that the expressions of PCNA and iNOS were induced by DEN plus PB in liver tissues. Oral administration of berberine (50 mg/kg) inhibited the hepatocyte proliferation and iNOS expression, decreased cytochrome P450 content, inhibited activities of CYP2E1 and CYP1A2 in DEN-plus-PB-treated rats in vivo. Moreover, berberine (10, 50 and 100 μM) inhibited the activities of CYP2E1 and CYP1A2 in microsomes isolated from DEN-plus-PB-treated rats in vitro, suggesting that anti-hepatocarcinogenetic potential of berberine might be due to inhibiting oxidative metabolic activities of CYP 2E1 and CYP1A2, and decreasing NO production in rats.