Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Japan.
Arch Toxicol. 2011 Mar;85(3):199-207. doi: 10.1007/s00204-010-0584-y. Epub 2010 Sep 17.
Oral helminthic mebendazole (MBZ) has been reported to cause liver injury with inflammatory responses. However, the underlying mechanism remains unknown. To examine the inflammatory reactions, we investigated whether MBZ and other helminthic drugs increase the release of pro-inflammatory cytokines and chemokines using human monocytic cells. The release of interleukin (IL)-8 and tumor necrosis factor (TNF) α from human monocytic THP-1 cells was significantly increased by treatment with MBZ, albendazole (ABZ), fenbendazole (FBZ), or oxibendazole (OBZ), but not by albendazole sulfoxide or praziquantel, suggesting that MBZ and structurally similar drugs can stimulate monocytes and increase the release of pro-inflammatory cytokines. MBZ also significantly increased the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) 1/2 in THP-1 cells. Pretreatment with the MAP kinase/ERK kinase 1/2 inhibitor U0126 significantly suppressed the increase of IL-8 and TNFα levels by MBZ, ABZ, FBZ, or OBZ treatment in THP-1 cells, but the p38 mitogen-activated protein kinase inhibitor SB203580 or JNK1/2 inhibitor SP600125 did not. These results suggested that an ERK1/2 pathway plays an important role in the release of IL-8 and TNFα in THP-1 cells treated with MBZ and structurally similar drugs. In conclusion, the release of inflammatory mediators by MBZ might be one of the mechanisms underlying immune-mediated liver injury. This in vitro method may be useful to predict adverse inflammatory reactions that lead to hepatotoxicity.
口服驱肠虫药甲苯咪唑（MBZ）已被报道可引起具有炎症反应的肝损伤。然而，其潜在机制尚不清楚。为了研究炎症反应，我们研究了 MBZ 和其他驱肠虫药是否会通过人单核细胞增加促炎细胞因子和趋化因子的释放。MBZ、阿苯达唑（ABZ）、芬苯达唑（FBZ）或奥芬达唑（OBZ）处理可显著增加人单核细胞 THP-1 细胞释放白细胞介素（IL）-8 和肿瘤坏死因子（TNF）α，但阿苯达唑亚砜或吡喹酮则不然，这表明 MBZ 和结构类似的药物可刺激单核细胞并增加促炎细胞因子的释放。MBZ 还可显著增加 THP-1 细胞中细胞外信号调节激酶（ERK）1/2 和 c-Jun N-末端激酶（JNK）1/2 的磷酸化。MAP 激酶/ERK 激酶 1/2 抑制剂 U0126 预处理可显著抑制 MBZ、ABZ、FBZ 或 OBZ 处理 THP-1 细胞中 IL-8 和 TNFα 水平的升高，但 p38 丝裂原活化蛋白激酶抑制剂 SB203580 或 JNK1/2 抑制剂 SP600125 则没有。这些结果表明，ERK1/2 通路在 MBZ 和结构类似的药物处理的 THP-1 细胞中 IL-8 和 TNFα 的释放中发挥重要作用。总之，MBZ 释放炎症介质可能是免疫介导肝损伤的机制之一。这种体外方法可能有助于预测导致肝毒性的不良炎症反应。
