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.
Ito
K
K
Department of Pathological Biochemistry, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Ozasa
H
H
Sanada
K
K
Horikawa
S
S
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004317:Doxorubicin / Q000627:therapeutic use*; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000378:metabolism; D051547:Heme Oxygenase-1; D007275:Injections, Intravenous; D007511:Ischemia / Q000473:pathology*; D019194:Ischemic Preconditioning; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008102:Liver Circulation / Q000187:drug effects*; D008297:Male; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000473:pathology*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011524:Protoporphyrins; C017803:zinc protoporphyrin; D004317:Doxorubicin; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1