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

Abstract

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, zincprotoporphyrin 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. (HEPATOLOGY 2000;31:416-419.)

A cytotoxic drug against reperfusion injury?

“…In the case of major hepatectomy performed under inflow occlusion, the technique of ischemic preconditioning does not prolong surgery since it can be done while preparing the liver for resection. 11 The report by Ito et al 34 reinforces the general point that preconditioning is a promising approach for preventing reperfusion injury. It will be important to learn more about the molecular mechanisms involved, towards developing safer and more effective methods of exploiting its clinical benefit.…”

“…37 Based on this indirect evidence, Yamamoto et al 35 suggested that the administration of doxorubicin before liver surgery may improve postoperative liver function in addition to the desired chemotherapeutic effects. Ito et al 34 extended these early findings by examining the involvement of HO-1.…”

“…38 Accumulating evidence suggests that effective protection against ischemia and reperfusion injury related to a preconditioning strategy needs to occur early, possibly on reperfusion of the organ. The study by Ito et al 34 does not exclude protective effects at an earlier stage of reperfusion, which might be independent of the heme oxygenase system. An earlier window of protection would confirm previous data in the heart that preconditioning may confer protection at two different intervals, one on reperfusion or soon after and the second several hours after the injury.…”

“…The study by Ito et al 34 reveals some intriguing findings regarding the time course of hepato-protection. HO-1 expression was first detected after 6 hours of reperfusion and then peaked between 18 and 24 hours.…”

“…In this issue of HEPATOLOGY, Ito et al 34 used a rat model to investigate the pharmacological activation of the HO system and its role in preventing ischemia and reperfusion injury. They induced HO activity using the anticancer drug, doxorubicin, which induces HO-1 expression in an indirect fashion through generation of oxygen-free radicals.…”