Dynamic changes of cyclophosphamide-induced liver injury in mice
10.16438/j.0513-4870.2019-0237
- VernacularTitle:环磷酰胺所致小鼠肝损伤的动态变化
- Author:
Can HUANG
1
;
Fa-jing HE
1
;
Xiao YANG
1
;
Li-huan GUAN
1
;
Si-min ZHANG
1
;
Yan-ying ZHOU
1
;
Shi-cheng FAN
1
;
Xin-peng YAO
1
;
Min HUANG
1
;
Hui-chang BI
1
Author Information
1. Lab of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Guangzhou 510006, China
- Publication Type:Research Article
- Keywords:
cyclophosphamide;
liver injury;
oxidative stress;
nuclear factor-erythroid 2-related factor 2
- From:
Acta Pharmaceutica Sinica
2019;54(6):1062-1068
- CountryChina
- Language:Chinese
-
Abstract:
Cyclophosphamide (CPA) is one of the most commonly used alkylating agents in the treatment of malignant cancer. CPA is metabolized by cytochrome P450 enzymes into 4-hydroxycyclophosphamide in vivo which can exhibit anti-tumor activity. Metabolic activation of CPA can cause adverse reactions such as myelosuppression, cystitis, and liver injury. The aim of this study was to evaluate the dynamic changes of hepatic injury induced by CPA in mice. Male BALB/c mice were injected CPA (200 mg·kg-1) intraperitoneally. Both serum and liver samples were collected at 0, 2, 6, 12 and 24 hours after dosing. The animal experiment protocol was approved by the Institutional Animal Care and Use Committee at Sun Yat-sen University. The results showed that hepatotoxicity was observed at 2 hours after CPA dosing, and the most serious liver injury was measured at 12 hours. The level of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and malondialdehyde (MDA) was significantly increased, glutathione (GSH) level was significantly decreased, hepatocyte edema and vacuolar degeneration were widely observed in liver tissue, and began to recover 24 hours after dosing. In addition, due to oxidative stress damage caused by CPA, nuclear factor-erythroid 2-related factor 2 (NRF2) signaling pathway was activated and the mRNA and protein expression of its downstream targets such as quinine oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic subunit (GCLC) and glutamate cysteine modifier subunit (GCLM) were up-regulated, which alleviated oxidative stress injury. In a summary, this study demonstrate the dynamic change of CPA-induced liver injury and the NRF2-mediated protective mechanisms, providing new insights into the CPA-induced liver injury.
