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Evaluation of Trace Elements in Augmentation of Statin-Induced Cytotoxicity in Uremic Serum-Exposed Human Rhabdomyosarcoma Cells

1
Research & Development Division, Towa Pharmaceutical Co., Ltd., Kyoto Research Park KISTIC#202, 134 Chudoji Minami-Machi, Shimogyo-ku, Kyoto 600-8813, Japan
2
Department of Clinical Pharmacy, Faculty of Pharmaceutical Science, Kyoto Pharmaceutical University, 5 Misasagi Nakauchi-cho, Yamashina-ku, Kyoto 607-8414, Japan
3
Department of Pharmacy Service, Shirasagi Hospital, 7-11-23 Kumata, Higashisumiyoshi-ku, Osaka 546-0002, Japan
4
Department of Medicine, Shirasagi Hospital, 7-11-23 Kumata, Higashisumiyoshi-ku, Osaka 546-0002, Japan
*
Author to whom correspondence should be addressed.
Toxins 2018, 10(2), 53; https://doi.org/10.3390/toxins10020053
Received: 29 November 2017 / Revised: 12 January 2018 / Accepted: 23 January 2018 / Published: 25 January 2018
(This article belongs to the Section Uremic Toxins)
Patients with end-stage kidney disease (ESKD) are at higher risk for rhabdomyolysis induced by statin than patients with normal kidney function. Previously, we showed that this increase in the severity of statin-induced rhabdomyolysis was partly due to uremic toxins. However, changes in the quantity of various trace elements in ESKD patients likely contribute as well. The purpose of this study is to determine the effect of trace elements on statin-induced toxicity in rhabdomyosarcoma cells exposed to uremic serum (US cells) for a long time. Cell viability, apoptosis, mRNA expression, and intracellular trace elements were assessed by viability assays, flow cytometry, real-time RT-PCR, and ICP-MS, respectively. US cells exhibited greater simvastatin-induced cytotoxicity than cells long-time exposed with normal serum (NS cells) (non-overlapping 95% confidence intervals). Intracellular levels of Mg, Mn, Cu, and Zn were significantly less in US cells compared to that in NS cells (p < 0.05 or 0.01). Pre-treatment with TPEN increased simvastatin-induced cytotoxicity and eliminated the distinction between both cells of simvastatin-induced cytotoxicity. These results suggest that Zn deficiencies may be involved in the increased risk for muscle complaints in ESKD patients. In conclusion, the increased severity of statin-induced rhabdomyolysis in ESKD patients may be partly due to trace elements deficiencies. View Full-Text
Keywords: end-stage kidney disease; uremic serum; simvastatin; cytotoxicity; zinc; rhabdomyolysis end-stage kidney disease; uremic serum; simvastatin; cytotoxicity; zinc; rhabdomyolysis
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Uchiyama, H.; Tsujimoto, M.; Shimada, N.; Tsutsui, K.; Nitta, A.; Yoshida, T.; Furukubo, T.; Izumi, S.; Yamakawa, T.; Tachiki, H.; Minegaki, T.; Nishiguchi, K. Evaluation of Trace Elements in Augmentation of Statin-Induced Cytotoxicity in Uremic Serum-Exposed Human Rhabdomyosarcoma Cells. Toxins 2018, 10, 53.

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