Increased glutathione levels and activity of PON1 (phenyl acetate esterase) in the liver of rats after a single dose of cyclophosphamide: A defense mechanism?
Increased glutathione levels and activity of PON1 (phenyl acetate esterase) in the liver of rats after a single dose of cyclophosphamide: A defense mechanism?
复制标题
DOI：
10.1016/j.etp.2007.06.006
复制
发表时间：
2008-03-01
影响因子：
--
通讯作者：
Sugumar, Emila
中科院分区：
文献类型：
--
作者：
Abraham, Premila;Sugumar, Emila
环磷酰胺（CYP）作为抗癌药物的临床应用受到其尿毒性和肾毒性的限制，并且在较小程度上受到其肝毒性的限制。本研究旨在找出肝脏虽然是药物活化和代谢的主要部位，但在这三个器官中对CYP引起的损伤最不敏感的原因。体重200-250g的成年雌性Wistar大鼠以150mg/kg体重的剂量单次腹腔注射CYP，并在CYP给药后6、16或24小时的不同时间间隔处死。对照大鼠仅施用盐水。通过测量血浆丙氨酸氨基转移酶（ALT）活性和肝脏的组织病理学来评估肝毒性。肝脏用于还原型谷胱甘肽的测定；对氧磷酶 (PON1) 丙二醛的活性 - 脂质过氧化的标志物。血清用于测定ALT活性和PON1活性。肝脏CYP治疗大鼠的还原型谷胱甘肽水平在16和24小时分别增加22%和57%。有趣的是，在治疗 24 小时后，在 CYP 治疗的大鼠的肝脏中观察到 PON1 活性显着增加（122%）。与此同时，血清中 PON1 活性显着增加 (23%)。在治疗后的任何时间段均未观察到肝脏丙二醛水平的显着变化。 CYP治疗后血清ALT活性略有增加24 It。使用该药物治疗后仅 24 小时，就在组织学上观察到轻度肝损伤。本研究首次表明，肝脏中抗氧化剂水平的增加可能是预防/最小化 CYP 诱导的肝损伤的防御机制。 (C) 2007 爱思唯尔有限公司。版权所有。
The clinical utility of cyclophosphamide (CYP) as an anticancer drug is limited by its urotoxicity and nephrotoxicity and to a lesser extent by its hepatotoxicity. The present study was undertaken in order to find out the reason why liver is least susceptible of the three organs to CYP-induced damage although it is the major site for drug activation and metabolism.Adult female Wistar rats weighing 200-250 g were administered single intraperitoneal injection of CYP at the dose of 150 mg/kg body weight and sacrificed at various time intervals 6, 16 or 24 h after the dose of CYP. The control rats were administered saline alone. Hepatotoxicity was assessed by measuring plasma alanine aminotransferase (ALT) activity and histopathology of the liver. Liver was used for the assay of reduced glutathione; activity of paraoxonase (PON1) malondialdehyde - marker of lipid peroxidation. Serum was used for the assay of ALT activity and PON1 activity.The level of reduced glutathione in the liver CYP treated rat was increased by 22% and 57% at 16 and 24h, respectively. Interestingly, a marked increase in the activity of PON1 (122%) was observed in the livers of CYP treated rats 24h after treatment. This was accompanied by significant increase in PON1 activity (23%) in the serum. No significant alteration in hepatic malondialdehyde level was observed at any time period after treatment. Serum ALT activity was increased slightly 24 It after treatment with CYP. Mild liver damage was observed histologically only 24 h after treatment with the drug.The present investigation shows for the first time that an increase in antioxidant levels in the liver may be a defense mechanism to prevent/minimize CYP-induced liver damage. (C) 2007 Elsevier GmbH. All rights reserved.