Pharmacological preconditioning with doxorubicin: Implications of heme oxygenase-1 induction in doxorubicin-induced hepatic injury in rats

Heme oxygenase (HO) is the rate-limiting enzyme in the degradation of heme into biliverdin, carbon monoxide, and iron. HO-1, an inducible form, is tho ught to contribute to resistance to various types of oxidative stress. Doxo rubicin (DOX) produces clinically useful responses in a variety of human ca ncers. We reported previously that prior administration of DOX ameliorated subsequent hepatic ischemia and reperfusion injury. The aim of this study w as to examine whether this pharmacological preconditioning was useful for a nother type of hepatic injury induced by a non-surgical method. When a high dose of DOX (10 mg/kg body weight) was administered directly to rat liver via the portal vein, serum aspartate transaminase (AST) and alanine transam inase (ALT) levels increased markedly 24 hr after the injection. Under this condition, zinc-protoporphyrin IX, a specific inhibitor of HO-1, caused. b oth serum AST and ALT levels to be elevated further. When a low dose of DOX (5 mg/kg body weight) was administered to rats via the tail vein as pharma cological preconditioning 3 days before the injection of a high dose of DOX via the portal vein, the levels of serum AST and ALT in rats clearly were improved as compared with rats without the preconditioning. Expression of H O-1 in the liver was confirmed 3 days after the administration of a low dos e of DOX. In addition, prior administration of zinc-protoporphyrin IX aboli shed the effect of DOX preconditioning. Immunohistochemical analysis showed that the positive staining of HO-1 protein induced by a low dose of DOX wa s localized to histiocytes infiltrating periportal areas. These results str ongly suggest that pharmacological preconditioning with DOX may generally h elp to attenuate subsequent oxidant-induced hepatic injury. (C) 2001 Elsevi er Science Inc. All rights reserved.