Ito K, Ozasa H, Nagashima Y, Hagiwara K, Horikawa S
Department of Pathological Biochemistry, Medical Research Institute, Tokyo Medical and Dental University, 2-3-10 Kanda-surugadai, Chiyoda-ku, 101-0062, Tokyo, Japan.
Biochem Pharmacol. 2001 Nov 1;62(9):1249-55. doi: 10.1016/s0006-2952(01)00766-3.
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 thought to contribute to resistance to various types of oxidative stress. Doxorubicin (DOX) produces clinically useful responses in a variety of human cancers. We reported previously that prior administration of DOX ameliorated subsequent hepatic ischemia and reperfusion injury. The aim of this study was to examine whether this pharmacological preconditioning was useful for another 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 transaminase (ALT) levels increased markedly 24 hr after the injection. Under this condition, zinc-protoporphyrin IX, a specific inhibitor of HO-1, caused both 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 pharmacological 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 HO-1 in the liver was confirmed 3 days after the administration of a low dose of DOX. In addition, prior administration of zinc-protoporphyrin IX abolished the effect of DOX preconditioning. Immunohistochemical analysis showed that the positive staining of HO-1 protein induced by a low dose of DOX was localized to histiocytes infiltrating periportal areas. These results strongly suggest that pharmacological preconditioning with DOX may generally help to attenuate subsequent oxidant-induced hepatic injury.
血红素加氧酶（HO）是血红素降解为胆绿素、一氧化碳和铁过程中的限速酶。诱导型的HO-1被认为有助于抵抗各种类型的氧化应激。阿霉素（DOX）在多种人类癌症中产生临床上有用的反应。我们之前报道过，预先给予DOX可改善随后的肝脏缺血再灌注损伤。本研究的目的是检查这种药物预处理对于另一种由非手术方法诱导的肝损伤是否有用。当通过门静脉将高剂量的DOX（10毫克/千克体重）直接注射到大鼠肝脏时，注射后24小时血清天冬氨酸转氨酶（AST）和丙氨酸转氨酶（ALT）水平显著升高。在这种情况下，HO-1的特异性抑制剂锌原卟啉IX导致血清AST和ALT水平进一步升高。当在通过门静脉注射高剂量DOX前3天，经尾静脉给大鼠注射低剂量的DOX作为药物预处理时，与未进行预处理的大鼠相比，大鼠血清AST和ALT水平明显改善。在给予低剂量DOX 3天后，肝脏中HO-1的表达得到证实。此外，预先给予锌原卟啉IX消除了DOX预处理的效果。免疫组织化学分析表明，低剂量DOX诱导的HO-1蛋白阳性染色定位于门静脉周围浸润的组织细胞。这些结果强烈表明，DOX药物预处理通常可能有助于减轻随后的氧化剂诱导的肝损伤。
