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

Doxorubicin produces clinically useful responses in a variety of human canc ers. However, the toxicity of doxorubicin has limited its usefulness. This side effect is mainly due to the doxorubicin-mediated free radical formatio n. Administration of doxorubicin (10 mg/kg body weight) to rats intravenous ly induces heme oxygenase-l (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 th e injection. It is known that HO-1 plays a protective role against the oxid ative injury. Therefore, we have examined the protective effect of doxorubi cin preconditioning against the hepatic ischemia-reperfusion injury. Partia l 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/k g body weight) was intravenously administered to rats 2 days before the isc hemia, the serum alanine transaminase (ALT) levels in the preconditioning r at were clearly improved compared with those in the rat without preconditio ning. Under this situation, zinc-protoporphyrin IX, a specific inhibitor of HO-1, was injected subcutaneously to rats at 3 and 16 hours before the isc hemia, the ALT levels were not improved by doxorubicin preconditioning. His topathologic examination also supported these results, Although the HO-1 pr otein level was fairly low 2 days after the doxorubicin administration, sig nificant amounts of HO-1 protein were detected. Our results indicated that the induction of HO-1 played a protective role against hepatic ischemia-rep erfusion injury and that doxorubicin preconditioning is more clinically use ful than other preconditioning methods.