{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:56:09Z","timestamp":1760241369665,"version":"build-2065373602"},"reference-count":19,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2018,1,25]],"date-time":"2018-01-25T00:00:00Z","timestamp":1516838400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Strategic Research Foundation","award":["S1201008"],"award-info":[{"award-number":["S1201008"]}]},{"name":"Grant-in-Aid for Scientific Research","award":["15K08601"],"award-info":[{"award-number":["15K08601"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>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 &lt; 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.<\/jats:p>","DOI":"10.3390\/toxins10020053","type":"journal-article","created":{"date-parts":[[2018,1,25]],"date-time":"2018-01-25T12:25:49Z","timestamp":1516883149000},"page":"53","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Evaluation of Trace Elements in Augmentation of Statin-Induced Cytotoxicity in Uremic Serum-Exposed Human Rhabdomyosarcoma Cells"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9505-1182","authenticated-orcid":false,"given":"Hitoshi","family":"Uchiyama","sequence":"first","affiliation":[{"name":"Research & Development Division, Towa Pharmaceutical Co., Ltd., Kyoto Research Park KISTIC#202, 134 Chudoji Minami-Machi, Shimogyo-ku, Kyoto 600-8813, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1325-8329","authenticated-orcid":false,"given":"Masayuki","family":"Tsujimoto","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Faculty of Pharmaceutical Science, Kyoto Pharmaceutical University, 5 Misasagi Nakauchi-cho, Yamashina-ku, Kyoto 607-8414, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naomi","family":"Shimada","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Faculty of Pharmaceutical Science, Kyoto Pharmaceutical University, 5 Misasagi Nakauchi-cho, Yamashina-ku, Kyoto 607-8414, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koji","family":"Tsutsui","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Faculty of Pharmaceutical Science, Kyoto Pharmaceutical University, 5 Misasagi Nakauchi-cho, Yamashina-ku, Kyoto 607-8414, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayaka","family":"Nitta","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Faculty of Pharmaceutical Science, Kyoto Pharmaceutical University, 5 Misasagi Nakauchi-cho, Yamashina-ku, Kyoto 607-8414, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takuya","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Faculty of Pharmaceutical Science, Kyoto Pharmaceutical University, 5 Misasagi Nakauchi-cho, Yamashina-ku, Kyoto 607-8414, Japan"},{"name":"Department of Pharmacy Service, Shirasagi Hospital, 7-11-23 Kumata, Higashisumiyoshi-ku, Osaka 546-0002, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taku","family":"Furukubo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Service, Shirasagi Hospital, 7-11-23 Kumata, Higashisumiyoshi-ku, Osaka 546-0002, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satoshi","family":"Izumi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Service, Shirasagi Hospital, 7-11-23 Kumata, Higashisumiyoshi-ku, Osaka 546-0002, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoyuki","family":"Yamakawa","sequence":"additional","affiliation":[{"name":"Department of Medicine, Shirasagi Hospital, 7-11-23 Kumata, Higashisumiyoshi-ku, Osaka 546-0002, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hidehisa","family":"Tachiki","sequence":"additional","affiliation":[{"name":"Research & Development Division, Towa Pharmaceutical Co., Ltd., Kyoto Research Park KISTIC#202, 134 Chudoji Minami-Machi, Shimogyo-ku, Kyoto 600-8813, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tetsuya","family":"Minegaki","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Faculty of Pharmaceutical Science, Kyoto Pharmaceutical University, 5 Misasagi Nakauchi-cho, Yamashina-ku, Kyoto 607-8414, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kohshi","family":"Nishiguchi","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Faculty of Pharmaceutical Science, Kyoto Pharmaceutical University, 5 Misasagi Nakauchi-cho, Yamashina-ku, Kyoto 607-8414, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,1,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1017\/S031716710001564X","article-title":"Effect of statin on progression of symptomatic intracranial atherosclerosis","volume":"39","author":"Kim","year":"2012","journal-title":"Can. J. Neurol. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1053\/j.ackd.2005.01.007","article-title":"Effects of statin therapy on the progression of chronic kidney disease","volume":"12","author":"Shah","year":"2005","journal-title":"Adv. Chronic Kidney Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1056\/NEJM199511163332001","article-title":"Prevention of coronary heart disaease with pravastatin in men with hypercholesterolemia","volume":"333","author":"Shepherd","year":"1995","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1136\/bmj.39472.580984.AE","article-title":"Effects of statins in patients with chronic kidney disease: Meta-analysis and meta-regression of randomised controlled trials","volume":"336","author":"Strippoli","year":"2008","journal-title":"BMJ"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1002\/pds.1287","article-title":"Risk factors for statin-associated rhabdomyolysis","volume":"16","author":"Schech","year":"2007","journal-title":"Pharmacoepidemiol. Drug Saf."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2612","DOI":"10.3390\/toxins6092612","article-title":"Uremic toxins enhance statin-induced cytotoxicity in differentiated human rhabdomyosarcoma cells","volume":"6","author":"Uchiyama","year":"2014","journal-title":"Toxins"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.3390\/toxins5081475","article-title":"Effects of decreased vitamin D and accumulated uremic toxin on human CYP3A4 activity in patients with end-stage renal disease","volume":"5","author":"Tsujimoto","year":"2013","journal-title":"Toxins"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1016\/j.clinthera.2014.02.023","article-title":"Low vitamin D as a risk factor for the development of myalgia in patients taking high-dose simvastatin: A retrospective review","volume":"36","author":"Mergenhagen","year":"2014","journal-title":"Clin. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1007\/s12011-011-9103-0","article-title":"The correlation of serum trace elements and heavy metals with carotid artery atherosclerosis in maintenance hemodialysis patients","volume":"144","author":"Ari","year":"2011","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"79","DOI":"10.7150\/ijms.5291","article-title":"Effects of zinc supplementation on plasma copper\/zinc ratios, oxidative stress, and immunological status in hemodialysis patients","volume":"10","author":"Guo","year":"2013","journal-title":"Int. J. Med. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1089\/ars.2014.6190","article-title":"Statins Trigger Mitochondrial ROS-Induced Apoptosis in Glycolytic Skeletal Muscle","volume":"24","author":"Bouitbir","year":"2016","journal-title":"Antioxid. Redox Signal."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1016\/S0024-3205(01)01252-8","article-title":"Increased apoptosis in a variety of tissues of zinc-deficient rats","volume":"69","author":"Nodera","year":"2001","journal-title":"Life Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1039\/C0MB00166J","article-title":"Suppression of statin effectiveness by copper and zinc in yeast and human cells","volume":"7","author":"Fowler","year":"2011","journal-title":"Mol. Biosyst."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2649","DOI":"10.1681\/ASN.2007070792","article-title":"Mechanism of hypokalemia in magnesium deficiency","volume":"18","author":"Huang","year":"2007","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1136\/bmj.327.7407.115","article-title":"Rhabdomyolysis","volume":"327","author":"Lane","year":"2003","journal-title":"BMJ"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2167","DOI":"10.1021\/bi982284u","article-title":"A structure-based mechanism for copper-zinc superoxide dismutase","volume":"38","author":"Hart","year":"1999","journal-title":"Biochemistry"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1152\/japplphysiol.00107.2011","article-title":"Atorvastatin treatment reduces exercise capacities in rats: Involvement of mitochondrial impairments and oxidative stress","volume":"111","author":"Bouitbir","year":"2011","journal-title":"J. Appl. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1177\/153537020623100916","article-title":"Cytotoxicity of nitric oxide is alleviated by zinc-mediated expression of antioxidant genes","volume":"231","author":"Chung","year":"2006","journal-title":"Exp. Biol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.1016\/j.bcp.2003.08.011","article-title":"Comparing myotoxic effects of squalene synthase inhibitor, T-91485, and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in human myocytes","volume":"66","author":"Nishimoto","year":"2003","journal-title":"Biochem. 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