caa a22 4500 445853190 CHVBK 20180317145419.0 cr unu---uuuuu 170323e20111201xx s 000 0 eng 10.1007/s00204-011-0700-7 doi (NATIONALLICENCE)springer-10.1007/s00204-011-0700-7 Rat H9c2 cardiac myocytes are sensitive to arsenite due to a modest activation of transcription factor Nrf2 [Elektronische Daten] [Daigo Sumi, Takahiko Sasaki, Hideki Miyataka, Seiichiro Himeno] The mechanism underlying the hepatotoxicity induced by arsenic exposure is well investigated. However, little is known about the detailed mechanisms of arsenic-induced cardiotoxicity or cardiac factors involved in high sensitivity to arsenicals in spite of the fact that arsenic trioxide, which is used to treat acute promyelocytic leukemia, causes cardiotoxicity. Here, we show that rat H9c2(2-1) cardiac myocytes exhibit high sensitivity to inorganic arsenite (As(III)) as compared with rat-derived four cell lines (liver epithelial TRL1215 cells, kidney epithelial NRK-52E cells, PC12 phechromocytoma cells and C6 glioma cells). Furthermore, we found a lower steady-state level of glutathione and glutamyl-cysteine ligase (GCL) in H9c2(2-1) cells compared with TRL1215 cells, resulting in an increase in arsenic accumulation. In addition, we detected that the up-regulation of GCL and multi-drug resistance-associated protein (MRP) caused by As(III) was extremely low in H9c2(2-1) cells compared with TRL1215 cells. It is known that Nrf2, which regulates GCL and MRP expression, plays an important role in the protection of cells from arsenicals. We investigated the participation of Nrf2 in the difference of sensitivity to arsenicals between H9c2(2-1) and TRL1215 cells and found that Nrf2 was clearly activated by As(III) exposure in TRL1215 cells but only poorly activated in H9c2(2-1) cells. Considering these results together, we propose that modest activation of Nrf2 during exposure to As(III) in H9c2(2-1) cardiac myocytes leads to reduced ability to metabolize and excrete arsenic. Springer-Verlag, 2011 Arsenic nationallicence Nrf2 nationallicence Glutathione nationallicence MRP nationallicence As(III) : Inorganic arsenite nationallicence BSO : Buthionine sulfoximine nationallicence GCLC : Glutamyl-cysteine ligase catalytic subunit nationallicence GCLM : Glutamyl-cysteine ligase modulatory subunit nationallicence GSH : Glutathione nationallicence ICP-MS : Inductively coupled plasma mass spectrometry nationallicence Keap1 : Kelch-like ECH-associated protein 1 nationallicence MRP : Multi-drug resistance-associated protein nationallicence Nrf2 : NF-E2-related factor-2 nationallicence Sumi Daigo Laboratory of Molecular Nutrition and Toxicology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 770-8514, Yamashiro-cho, Tokushima, Japan aut Sasaki Takahiko Laboratory of Molecular Nutrition and Toxicology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 770-8514, Yamashiro-cho, Tokushima, Japan aut Miyataka Hideki Laboratory of Molecular Nutrition and Toxicology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 770-8514, Yamashiro-cho, Tokushima, Japan aut Himeno Seiichiro Laboratory of Molecular Nutrition and Toxicology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 770-8514, Yamashiro-cho, Tokushima, Japan aut Archives of Toxicology Springer-Verlag 85/12(2011-12-01), 1509-1516 0340-5761 85:12<1509 2011 85 204 https://doi.org/10.1007/s00204-011-0700-7 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00204-011-0700-7 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Sumi Daigo Laboratory of Molecular Nutrition and Toxicology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 770-8514, Yamashiro-cho, Tokushima, Japan aut NATIONALLICENCE 700 1- Sasaki Takahiko Laboratory of Molecular Nutrition and Toxicology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 770-8514, Yamashiro-cho, Tokushima, Japan aut NATIONALLICENCE 700 1- Miyataka Hideki Laboratory of Molecular Nutrition and Toxicology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 770-8514, Yamashiro-cho, Tokushima, Japan aut NATIONALLICENCE 700 1- Himeno Seiichiro Laboratory of Molecular Nutrition and Toxicology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 770-8514, Yamashiro-cho, Tokushima, Japan aut NATIONALLICENCE 773 0- Archives of Toxicology Springer-Verlag 85/12(2011-12-01), 1509-1516 0340-5761 85:12<1509 2011 85 204 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer