Doxorubicin preconditioning: A protection against rat hepatic ischemia‐reperfusion injury

Doxorubicin produces clinically useful responses in a variety of human cancers. However, the toxicity of doxorubicin has limited its usefulness. This side effect is mainly due to the doxorubicin‐mediated free radical formation. Administration of doxorubicin (10 mg/kg body weight) to rats intravenously induces heme oxygenase‐1 (HO‐1) in the liver. The levels of HO‐1 protein were first detected at 6 hours and peaked at about 18 to 24 hours after the injection. It is known that HO‐1 plays a protective role against the oxidative injury. Therefore, we have examined the protective effect of doxorubicin preconditioning against the hepatic ischemia‐reperfusion injury. Partial hepatic ischemia was produced in the left and medium lobes for 45 minutes followed by 120 minutes reperfusion. When low doses of doxorubicin (1 mg/kg body weight) was intravenously administered to rats 2 days before the ischemia, the serum alanine transaminase (ALT) levels in the preconditioning rat were clearly improved compared with those in the rat without preconditioning. Under this situation, zinc‐protoporphyrin IX, a specific inhibitor of HO‐1, was injected subcutaneously to rats at 3 and 16 hours before the ischemia, the ALT levels were not improved by doxorubicin preconditioning. Histopathologic examination also supported these results. Although the HO‐1 protein level was fairly low 2 days after the doxorubicin administration, significant amounts of HO‐1 protein were detected. Our results indicated that the induction of HO‐1 played a protective role against hepatic ischemia‐reperfusion injury and that doxorubicin preconditioning is more clinically useful than other preconditioning methods.

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