caa a22 4500 445853298 CHVBK 20180317145420.0 cr unu---uuuuu 170323e20110301xx s 000 0 eng 10.1007/s00204-010-0584-y doi (NATIONALLICENCE)springer-10.1007/s00204-010-0584-y Stimulation of pro-inflammatory responses by mebendazole in human monocytic THP-1 cells through an ERK signaling pathway [Elektronische Daten] [Katsuhiko Mizuno, Yasuyuki Toyoda, Tatsuki Fukami, Miki Nakajima, Tsuyoshi Yokoi] 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. Springer-Verlag, 2010 Mebendazole nationallicence THP-1 cell nationallicence Hepatotoxicity nationallicence IL-8 nationallicence TNFα nationallicence Mizuno Katsuhiko Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, 920-1192, Kanazawa, Japan aut Toyoda Yasuyuki Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, 920-1192, Kanazawa, Japan aut Fukami Tatsuki Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, 920-1192, Kanazawa, Japan aut Nakajima Miki Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, 920-1192, Kanazawa, Japan aut Yokoi Tsuyoshi Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, 920-1192, Kanazawa, Japan aut Archives of Toxicology Springer-Verlag 85/3(2011-03-01), 199-207 0340-5761 85:3<199 2011 85 204 https://doi.org/10.1007/s00204-010-0584-y text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00204-010-0584-y text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Mizuno Katsuhiko Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, 920-1192, Kanazawa, Japan aut NATIONALLICENCE 700 1- Toyoda Yasuyuki Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, 920-1192, Kanazawa, Japan aut NATIONALLICENCE 700 1- Fukami Tatsuki Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, 920-1192, Kanazawa, Japan aut NATIONALLICENCE 700 1- Nakajima Miki Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, 920-1192, Kanazawa, Japan aut NATIONALLICENCE 700 1- Yokoi Tsuyoshi Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, 920-1192, Kanazawa, Japan aut NATIONALLICENCE 773 0- Archives of Toxicology Springer-Verlag 85/3(2011-03-01), 199-207 0340-5761 85:3<199 2011 85 204 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer