Safrole-induced Oxidative Damage in the Liver of Sprague–Dawley Rats

Safrole is a weak hepatocarcinogen, and its carcinogenic effect has been linked to the formation of stable safrole–DNA adducts. In this study, we tested whether safrole also induces oxidative damages in Sprague–Dawley rats. By single ip injection, safrole dose-dependently induced the formation of hepatic lipid hydroperoxides (LHP) and 8-hydroxy-2′-deoxyguanosine (8-OH-dG). The safrole-induced LHP reached peak level on day 3 and gradually returned to the basal level on day 15. On the other hand, 8-OH-dG levels from the similarly treated rats peaked on day 5 and returned to basal level on day 15. Safrole also dose-dependently induced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities. We also examined the protective effect of vitamin E, deferoxamine and N-acetylcysteine against the safrole-induced oxidative damage. N-Acetylcysteine, the precursor of glutathione, exerted the greatest protective effect among the three antioxidants tested. In contrast, buthionine sulfoximine, the glutathione synthesis inhibitor, enhanced the safrole-induced oxidative damage, as evidenced by the elevation of LHP and 8-OH-dG levels on day 3 (P<0.05). These findings demonstrate that safrole treatment induces oxidative damage in rat hepatic tissue, and glutathione plays an important protective role. This oxidative damage may be involved in the hepatocarcinogenic effect of safrole.