Inhibition of ebselen on aflatoxin B₁-induced hepatocarcinogenesis in Fischer 344 rats

Aflatoxin B₁ (AFB₁), a potent hepatocarcinogen, enhances ROS formation and causes oxidative DNA damage, which may play a role in its carcinogenicity. We have demonstrated recently that ebselen, an organic selenium compound, protects against the cytotoxicity of AFB₁ through its antioxidant capability. The present study was designed to investigate the effect of ebselen on AFB₁-induced hepatocarcinogenesis in an animal model. Fischer 344 rats were first treated with either deionized water or ebselen (5 mg/kg, 5 days/week) via gavage for 4 weeks, then given AFB₁ (0.4 mg/kg, gavage, once a week) or AFB₁ plus ebselen (5 mg/kg, 5 days/week) for another 24 weeks. The results showed that the hepatocarcinogenicity of AFB₁ in rats was significantly reduced by ebselen treatment as indicated by a decrease in: (i) serum γ-glutamyl transpeptidase activity; (ii) expression of mRNAs of liver α-fetoprotein and the placental form of glutathione S-transferase (GST-P); and (iii) the area and mean density of staining of liver GST-P foci. Ebselen treatment significantly reduced the formation of hepatic AFB₁-DNA adducts and 8-hydroxydeoxyguanosine caused by AFB₁ exposure. These findings suggest that ebselen can inhibit the carcinogenicity of AFB₁. In addition to the reduction of AFB₁-DNA adduct formation, the protective effect of ebselen against AFB₁-induced oxidative DNA damage may also, at least in part, contribute to its anticarcinogenic property.