Establishment and characterization of a mouse model of rhabdomyolysis by coadministration of statin and fibrate
Establishment and characterization of a mouse model of rhabdomyolysis by coadministration of statin and fibrate
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DOI：
10.1016/j.toxlet.2019.03.001
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发表时间：
2019-06-01
影响因子：
3.5
通讯作者：
Yokoi, Tsuyoshi
中科院分区：
文献类型：
--
作者：
Watanabe, Katsuhito;Oda, Shingo;Yokoi, Tsuyoshi
横纹肌溶解症的特征是血浆肌酸磷酸激酶（CPK）水平升高，多器官功能障碍，尤其是肾功能衰竭，以及约50%的获得性横纹肌溶解症是由药物引起的。已知他汀类药物可引起横纹肌溶解，他汀类药物和贝特类药物联合给药时其发生率高出≥ 10倍。本研究的目的是通过他汀类药物与贝特类药物联合应用，建立药物性横纹肌溶解症的小鼠模型，以阐明其肌肉毒性的机制。我们将洛伐他汀（LV）和吉非罗齐（GF）与谷胱甘肽合成抑制剂L-丁硫氨酸-（S，R）-亚砜亚胺（BSO）一起给予C57 BL/6 J雌性小鼠，每天一次，持续3天。CPK和天冬氨酸氨基转移酶（AST）的血浆水平显著升高，血浆miR-206- 3 p和miR-133- 3 p水平升高（而非miR-122- 5 p和miR-208- 3 p水平升高）提示骨骼肌特异性毒性。在骨骼肌中，caspase 3/7活性和氧化应激相关因子的mRNA水平升高。药代动力学参数显示，他汀类药物的血药浓度显着增加，共同管理的GF。与临床横纹肌溶解症一样，检查肾损伤的可能性。在组织学检查中，在肾近端小管中观察到空泡，并且在LV和GF联合给药的小鼠中，血浆肾损伤标志物脂质运载蛋白2/中性粒细胞明胶酶相关脂质运载蛋白（Lcn 2/Ngal）显著增加，表明急性肾损伤的轻度并发症。使用本方法成功地进行了各种他汀类药物的肌毒性潜力的定量比较。本研究采用临床常用的他汀类药物与贝特类药物联合给药，建立横纹肌溶解症小鼠模型。这种小鼠模型可能有助于识别具有横纹肌溶解高风险的药物。
Rhabdomyolysis is characterized by elevation of plasma creatine phosphokinase (CPK) level, and multiple organ disorders, especially renal failure, as well as approximately 50% of acquired rhabdomyolysis are caused by pharmaceuticals. Statins are known to cause rhabdomyolysis, and its incidence is >= 10 times higher with coadministration of statin and fibrate. The purpose of this study is to establish a mouse model of drug-induced rhabdomyolysis by coadministration of statin and fibrate to clarify the mechanisms of its myotoxicity. We administered lovastatin (LV) and gemfibrozil (GF) with a glutathione synthesis inhibitor, L-buthionine-(S,R)-sulfoximine (BSO), to C57BL/6 J female mice once daily for 3 days. The plasma levels of CPK and aspartate aminotransferase (AST) were prominently increased, and the increase in plasma miR-206-3p and miR-133-3p levels, not the increase of miR-122-5p and miR-208-3p levels, suggested skeletal muscle-specific toxicity. The caspase 3/7 activity and mRNA levels of oxidative stress-related factors were elevated in skeletal muscle. Pharmacokinetic parameters showed that blood levels of statin were significantly increased by coadministered GF. The possibility of kidney injury was examined as in clinical rhabdomyolysis. In histological examination, vacuoles were observed in renal proximal tubules, and the plasma renal injury marker, lipocalin 2/neutrophil gelatinase-associated lipocalin (Lcn2/Ngal), was markedly increased in the mice coadministered LV and GF, suggesting mild complications of acute kidney injury. A quantitative comparison of the myotoxic potential of various statins was successfully performed using the present method. In this study, a rhabdomyolysis mouse model was established by coadministration of the clinically using statin and fibrate. This mouse model may be useful to identify drugs that have high risk for rhabdomyolysis.