Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
Drug Metab Dispos. 2011 Aug;39(8):1440-50. doi: 10.1124/dmd.111.039123. Epub 2011 May 13.
The use of doxorubicin (DOX) is limited by significant cardiotoxicity, nephrotoxicity, and hepatotoxicity. We have previously shown that DOX cardiotoxicity induces several cardiac cytochrome P450 (P450) enzymes with subsequent alteration in P450-mediated arachidonic acid metabolism. Therefore, in the current study, we investigated the effect of acute DOX toxicity on P450 expression and arachidonic acid metabolism in the kidney and liver of male Sprague-Dawley rats. Acute DOX toxicity was induced by a single intraperitoneal injection (15 mg/kg) of the drug. After 6 and 24 h, the kidneys and livers were harvested, and several P450 gene and protein expressions were determined by real-time polymerase chain reaction and Western blot analyses, respectively. Kidney and liver microsomal protein from control or DOX-treated rats was incubated with arachidonic acid, and its metabolites were determined by liquid chromatography-electron spray ionization-mass spectrometry. Our results showed that acute DOX toxicity caused an induction of CYP1B1 and CYP4A enzymes and an inhibition of CYP2B1 and CYP2C11 in both the kidney and liver. CYP2E1 was induced and soluble epoxide hydrolase (sEH) was inhibited in the kidney only. In addition, DOX toxicity caused a significant increase in epoxyeicosatrienoic acids formation in the kidney and a significant increase in 20-hydroxyeicosatetraenoic acid formation in both the kidney and the liver. In conclusion, acute DOX toxicity alters the expression of several P450 and sEH enzymes in an organ-specific manner. These changes can be attributed to DOX-induced inflammation and resulted in altered P450-mediated arachidonic acid metabolism.
阿霉素（DOX）的应用受到明显的心脏毒性、肾毒性和肝毒性的限制。我们之前已经表明，DOX 的心脏毒性会诱导几种心脏细胞色素 P450（P450）酶，随后改变 P450 介导的花生四烯酸代谢。因此，在目前的研究中，我们研究了急性 DOX 毒性对雄性 Sprague-Dawley 大鼠肾脏和肝脏中 P450 表达和花生四烯酸代谢的影响。通过单次腹腔注射（15mg/kg）药物诱导急性 DOX 毒性。在 6 和 24 小时后，收获肾脏和肝脏，并通过实时聚合酶链反应和 Western blot 分析分别确定几种 P450 基因和蛋白表达。用花生四烯酸孵育来自对照或 DOX 处理的大鼠的肾脏和肝脏微粒体蛋白，并通过液相色谱-电喷雾电离-质谱法测定其代谢物。我们的结果表明，急性 DOX 毒性导致 CYP1B1 和 CYP4A 酶的诱导以及 CYP2B1 和 CYP2C11 在肾脏和肝脏中的抑制。只有在肾脏中，CYP2E1 被诱导，可溶性环氧化物水解酶（sEH）被抑制。此外，DOX 毒性导致肾脏中环氧化二十碳三烯酸的形成显著增加，肾脏和肝脏中 20-羟二十碳四烯酸的形成显著增加。总之，急性 DOX 毒性以器官特异性的方式改变几种 P450 和 sEH 酶的表达。这些变化可归因于 DOX 诱导的炎症，导致 P450 介导的花生四烯酸代谢改变。
