Di Re J, Lee C, Riddick D S
Department of Pharmacology, University of Toronto, ON, Canada.
Can J Physiol Pharmacol. 1999 Aug;77(8):589-97.
Administration of the antineoplastic doxorubicin to rodents causes depression of hepatic cytochrome P450 (CYP) dependent biotransformation, an effect that has been partially attributed to the ability of doxorubicin to stimulate microsomal lipid peroxidation. Since doxorubicin can be bioactivated by the CYP/NADPH-CYP reductase system to products that bind covalently to microsomal protein, we hypothesized that doxorubicin functions as a mechanism-based inactivator of hepatic microsomal CYPs and (or) NADPH-CYP reductase under conditions in which doxorubicin-stimulated NADPH-dependent lipid peroxidation is minimized. In vitro studies were conducted with hepatic microsomes isolated from untreated and phenobarbital-treated male rats. Unlike the positive control carbon tetrachloride, doxorubicin (10 microM) did not stimulate NADPH-dependent lipid peroxidation in microsomal incubations containing EDTA (1.5 mM). Doxorubicin did not cause NADPH-dependent loss of microsomal CYP, heme, or steroid hydroxylation activities selective for CYP2A, CYP2B, CYP2C11, and CYP3A. The positive control 1-aminobenzotriazole caused marked NADPH-dependent decreases in all of these parameters. Neither doxorubicin nor 1-aminobenzotriazole caused NADPH-dependent loss of NADPH-CYP reductase activity, and neither compound altered the immunoreactive protein levels of CYP2B, CYP2C11, CYP3A, and NADPH-CYP reductase. These results indicate that a pharmacologically relevant concentration of doxorubicin does not cause direct mechanism-based inactivation of hepatic microsomal CYPs or NADPH-CYP reductase, suggesting that the ability of doxorubicin to depress hepatic CYP-mediated biotransformation in vivo is due to lipid peroxidation mediated heme destruction, altered heme metabolism, and (or) decreased expression of selected CYP enzymes.
给啮齿动物注射抗肿瘤药物阿霉素会导致肝微粒体细胞色素P450（CYP）依赖性生物转化作用受到抑制，这种作用部分归因于阿霉素刺激微粒体脂质过氧化的能力。由于阿霉素可被CYP/NADPH - CYP还原酶系统生物激活为能与微粒体蛋白共价结合的产物，我们推测在阿霉素刺激的NADPH依赖性脂质过氧化作用降至最低的条件下，阿霉素作为一种基于机制的肝微粒体CYP和（或）NADPH - CYP还原酶的失活剂发挥作用。使用从未经处理和经苯巴比妥处理的雄性大鼠分离得到的肝微粒体进行了体外研究。与阳性对照四氯化碳不同，在含有乙二胺四乙酸（EDTA，1.5 mM）的微粒体孵育体系中，阿霉素（10 microM）不会刺激NADPH依赖性脂质过氧化作用。阿霉素不会导致微粒体CYP、血红素或对CYP2A、CYP2B、CYP2C11和CYP3A具有选择性的类固醇羟化活性出现NADPH依赖性损失。阳性对照1 - 氨基苯并三唑导致所有这些参数出现显著的NADPH依赖性降低。阿霉素和1 - 氨基苯并三唑均不会导致NADPH - CYP还原酶活性出现NADPH依赖性损失，且两种化合物均未改变CYP2B、CYP2C11、CYP3A和NADPH - CYP还原酶的免疫反应性蛋白水平。这些结果表明，药理学相关浓度的阿霉素不会导致肝微粒体CYP或NADPH - CYP还原酶发生基于机制的直接失活，这表明阿霉素在体内抑制肝CYP介导的生物转化的能力是由于脂质过氧化介导的血红素破坏、血红素代谢改变和（或）所选CYP酶的表达降低。
