title: Uremic toxins enhance statin-induced cytotoxicity in differentiated human rhabdomyosarcoma cells.
abstract: The risk of myopathy and rhabdomyolysis is considerably increased in statin users with end-stage renal failure (ESRF). Uremic toxins, which accumulate in patients with ESRF, exert cytotoxic effects that are mediated by various mechanisms. Therefore, accumulation of uremic toxins might increase statin-induced cytotoxicity. The purpose of this study was to determine the effect of four uremic toxins-hippuric acid, 3-carboxy-4-methyl-5-propyl-2-furanpropionate, indole-3-acetic acid, and 3-indoxyl sulfate-on statin-induced myopathy. Differentiated rhabdomyosarcoma cells were pre-treated with the uremic toxins for seven days, and then the cells were treated with pravastatin or simvastatin. Cell viability and apoptosis were assessed by viability assays and flow cytometry. Pre-treatment with uremic toxins increased statin- but not cisplatin-induced cytotoxicity (p < 0.05 vs. untreated). In addition, the pre-treatment increased statin-induced apoptosis, which is one of the cytotoxic factors (p < 0.05 vs. untreated). However, mevalonate, farnesol, and geranylgeraniol reversed the effects of uremic toxins and lowered statin-induced cytotoxicity (p < 0.05 vs. untreated). These results demonstrate that uremic toxins enhance statin-induced apoptosis and cytotoxicity. The mechanism underlying this effect might be associated with small G-protein geranylgeranylation. In conclusion, the increased severity of statin-induced rhabdomyolysis in patients with ESRF is likely due to the accumulation of uremic toxins.
authors.affiliation: Pharmacovigilance and Post Marketing Surveillance Department, Towa Pharmaceutical Co. Ltd., 2-11, Shinbashi-cho, Kadoma, Osaka 571-8580, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Uchiyama
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmaceutical Science, Kyoto Pharmaceutical University, 5 Misasagi nakauchi-cho, Yamashina-ku, Kyoto 607-8414, Japan. tsujimt@mb.kyoto-phu.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tsujimoto
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmaceutical Science, Kyoto Pharmaceutical University, 5 Misasagi nakauchi-cho, Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Tadakazu
authors.initials: T
authors.lastname: Shinmoto
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmaceutical Science, Kyoto Pharmaceutical University, 5 Misasagi nakauchi-cho, Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Ogino
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmaceutical Science, Kyoto Pharmaceutical University, 5 Misasagi nakauchi-cho, Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Oda
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmaceutical Science, Kyoto Pharmaceutical University, 5 Misasagi nakauchi-cho, Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Department of Pharmacy Service, Shirasagi Hospital, 7-11-23 Kumata, Higashisumiyoshi-ku, Osaka 546-0002, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Furukubo
authors.affiliation: Department of Pharmacy Service, Shirasagi Hospital, 7-11-23 Kumata, Higashisumiyoshi-ku, Osaka 546-0002, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Izumi
authors.affiliation: Department of Medicine, Shirasagi Hospital, 7-11-23 Kumata, Higashisumiyoshi-ku, Osaka 546-0002, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Yamakawa
authors.affiliation: Research and Development Division, Towa Pharmaceutical Co. Ltd., Kyoto Research Park KISTIC#202, 134, Chudoji Minami-Machi, Shimogyo-ku, Kyoto 600-8813, Japan.
authors.forename: Hidehisa
authors.initials: H
authors.lastname: Tachiki
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmaceutical Science, Kyoto Pharmaceutical University, 5 Misasagi nakauchi-cho, Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Minegaki
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmaceutical Science, Kyoto Pharmaceutical University, 5 Misasagi nakauchi-cho, Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Kohshi
authors.initials: K
authors.lastname: Nishiguchi
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D005663:Furans / Q000494:pharmacology*; D006626:Hippurates / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007200:Indican / Q000494:pharmacology*; D007210:Indoleacetic Acids / Q000494:pharmacology*; D017035:Pravastatin / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology*; D012208:Rhabdomyosarcoma; D019821:Simvastatin / Q000494:pharmacology; D014118:Toxins, Biological / Q000494:pharmacology*; D014511:Uremia
chemical_list: D005663:Furans; D006626:Hippurates; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007210:Indoleacetic Acids; D011422:Propionates; D014118:Toxins, Biological; C030737:indoleacetic acid; C041693:3-carboxy-4-methyl-5-propyl-2-furanpropionic acid; D019821:Simvastatin; D017035:Pravastatin; D007200:Indican; C030514:hippuric acid