The antitripanocide Benznidazole promotes adaptive response to oxidative injury: Involvement of the nuclear factor-erythroid 2-related factor-2 (Nrf2) and multidrug resistance associated protein 2 (MRP2)
The antitripanocide Benznidazole promotes adaptive response to oxidative injury: Involvement of the nuclear factor-erythroid 2-related factor-2 (Nrf2) and multidrug resistance associated protein 2 (MRP2)
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2016
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通讯作者：
J. Rigalli;V. Perdomo;Nadia Ciriaci;D. Antonio;Francés;M. T. Ronco;A. Bataille;C. Ghanem;María;Laura Ruiz;J. Manautou;V. Catania
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作者：
J. Rigalli;V. Perdomo;Nadia Ciriaci;D. Antonio;Francés;M. T. Ronco;A. Bataille;C. Ghanem;María;Laura Ruiz;J. Manautou;V. Catania
氧化应激是导致药物性肝毒性的常见原因。苯并咪唑（BZL）是流行地区唯一可用于治疗恰加斯病的抗三唑类药物。它的使用与副作用有关，包括肝毒性生物标志物的增加。然而，BZL引起氧化应激的可能性研究得很少。在此，我们评估了在不同时间点，BZL相关浓度（200 μM）对人肝细胞系HepG2中氧化还原状态和抵消机制的影响。BZL在暴露1和3小时后增加了活性氧（ROS），使用Nrf2敲除小鼠证实了恢复参与，其中MRP2 mRNA表达不受BZL影响。总之，我们证明了BZL在HepG2细胞中的ROS增加以及谷胱甘肽过氧化物酶和MRP 2驱动的抵消机制，Nrf2是这种反应的关键调节剂。我们的结果可以解释与BZL治疗相关的肝脏改变。
Oxidative stress is a frequent cause underlying drug-induced hepatotoxicity. Benznidazole (BZL) is the only antitripanocide agent available for treatment of Chagas disease in endemic areas. Its use is associated with side effects, including increases in biomarkers of hepatotoxicity. However, BZL potential to cause oxidative stress has been poorly investigated. Here, we evaluated the effect of a pharmacologically relevant BZL concentration (200 μM) at different time points on redox status and the counteracting mechanisms in the human hepatic cell line HepG2. BZL increased reactive oxygen species (ROS) after 1 and 3 h of exposure, returning to participation was confirmed using Nrf2-knockout mice in which MRP2 mRNA expression was not affected by BZL. In summary, we demonstrated a ROS increase by BZL in HepG2 cells and a glutathione peroxidase- and MRP2 driven counteracting mechanism, being Nrf2 a key modulator of this response. Our results could explain hepatic alterations associated with BZL therapy.