The association between the regulation of L-lactic acid content in skeletal muscle cell involved in MCT and the mechanism of the drug-induced rhabdmyolysis
MCT参与的骨骼肌细胞L-乳酸含量调节与药物性横纹肌溶解症机制的关系
基本信息
- 批准号:16390155
- 负责人:
- 金额:$ 9.47万
- 依托单位:
- 依托单位国家:日本
- 项目类别:Grant-in-Aid for Scientific Research (B)
- 财政年份:2004
- 资助国家:日本
- 起止时间:2004 至 2006
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Firstly, we investigated whether MCT isoform contribute to the transport of L-lactic acid in L6 and RD cells as a model of rat and human skeletal muscle. We concluded that monocarboxylate transporter (MCT) 1 is responsible for L-lactic acid uptake and L-lactic acid efflux is mediated by MCT4 in L6 and RD cells. On the other hand, the effects of monocarboxylate dugs including HMG-CoA reductase inhibitors, statins, on MCT-mediated L-lactic acid transport system have not been elucidated. Therefore, we examined that the association between the effect of statins on L-lactic acid transport mediated by MCT and statins-induced intracellular acidification. Lipophilic satins, cerivastatin, simvastatin acid, fluvastatin, atorvastatin, lovastatin acid, pitavastatin reduced the number of viable cells and caused dramatic morphological changes and DNA fragmentation in a concentration- dependent manner. Moreover, lipophilic statins-induced apoptosis was associated with intracellular acidification and … More caspase-9 and -3/7 activation.To clarify the mechanism of statins-induced intracellular acidification, we examined the effect of statins on the efflux of L-lactic acid mediated by MCT4 from L6 and RD cells. Lipophilic statins inhibited the L-lactic acid efflux mediated by MCT4 from L6 and RD cells. On the other hand, hydrophilic statins, rosuvastatin and pravastatin had no effect on the efflux of L-lactic acid. Moreover, we established an MCT4 transfected cell line and to clarify the transport mechanism of L-lactic acid and the effects of statins on this transport system. Lipophilic statins significantly inhibited MCT4-mediated L-lactic acid transport in MCT4 transfected cells. On the contrary, hydrophilic statins had little effect on this transport system.Next, we tried to identify the compound suppressing statins-induced myopathy. Bicarbonate is clinically used for treatment of lactic acidosis and is involved in cellular pH regulation (alkalization). Since cerivastatin-induced apoptosis was associated with intracellular acidification, we therefore examined bicarbonate-induced improvement of statin-induced apoptosis. Bicarbonate suppressed cerivastatin-induced pH alteration, caspase activation, morphological change and reduction of RD and L6 cell viability. Moreover, bicarbonate prevented CPK levels increased by cerivastatin in vivo study. These results from in vitro and in vivo studies support that bicarbonate supplementation prevented statin-induced muscle damage. Less
首先,我们研究了作为大鼠和人骨骼肌模型的L 6和RD细胞中MCT亚型是否有助于L-乳酸的转运。我们得出结论,在L 6和RD细胞中,单羧酸转运蛋白(MCT)1负责L-乳酸摄取,而L-乳酸流出由MCT 4介导。另一方面,尚未阐明单羧酸药物(包括HMG-CoA还原酶抑制剂、他汀类药物)对MCT介导的L-乳酸转运系统的影响。因此,我们研究了他汀类药物对MCT介导的L-乳酸转运的影响与他汀类药物诱导的细胞内酸化之间的关系。亲脂性沙汀、西立伐他汀、辛伐他汀酸、氟伐他汀、阿托伐他汀、洛伐他汀酸、匹伐他汀以浓度依赖性方式减少活细胞的数量并引起显著的形态学变化和DNA片段化。此外,亲脂性他汀类药物诱导的细胞凋亡与细胞内酸化有关, ...更多信息 为了阐明他汀类药物诱导的细胞内酸化的机制,我们检查了他汀类药物对由MCT 4介导的L-乳酸从L 6和RD细胞流出的影响。亲脂性他汀类药物可抑制L 6和RD细胞中由MCT 4介导的L-乳酸外排。另一方面,亲水性他汀类药物、瑞舒伐他汀和普伐他汀对L-乳酸外排无影响。此外,我们建立了一个MCT 4转染细胞系,并阐明L-乳酸的转运机制和他汀类药物对该转运系统的影响。在MCT 4转染细胞中,亲脂性他汀类药物显著抑制MCT 4介导的L-乳酸转运。相反,亲水性他汀类药物对该转运系统几乎没有影响。接下来,我们试图鉴定抑制他汀类药物诱导的肌病的化合物。Biclidine在临床上用于治疗乳酸酸中毒,并参与细胞pH调节(碱化)。由于西伐他汀诱导的细胞凋亡与细胞内酸化有关,因此我们研究了碳酸氢盐诱导的他汀诱导的细胞凋亡的改善。Biclidine抑制西伐他汀诱导的pH改变,半胱天冬酶激活,形态学变化和RD和L 6细胞活力的降低。此外,体内研究中,碳酸氢盐可预防西立伐他汀引起的CPK水平升高。体外和体内研究的这些结果支持碳酸氢盐补充预防了他汀类药物诱导的肌肉损伤。少
项目成果
期刊论文数量(14)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Transport mechanism for L-lactic acid in human myocytes using human prototypic embryonal rhabdomyosarcoma cell Fine(RD cells).
使用人原型胚胎横纹肌肉瘤细胞 Fine(RD 细胞)的人肌细胞中 L-乳酸的转运机制。
- DOI:
- 发表时间:2005
- 期刊:
- 影响因子:0
- 作者:M.Kobayashi;I.Fujita;S.Itagaki;T.Hirano;K.Iseki
- 通讯作者:K.Iseki
Inhibitory effects of statins on human monocarboxylate transpoter 4.
他汀类药物对人单羧酸转运蛋白4的抑制作用。
- DOI:
- 发表时间:2006
- 期刊:
- 影响因子:0
- 作者:M.Kobayashi;Y.Otsuka;S.Itagaki;T.Hirano;K.Iseki
- 通讯作者:K.Iseki
Mechanism of L-lactic acid transport in L6 skeletal muscle cells.
- DOI:10.2133/dmpk.19.363
- 发表时间:2004-10-01
- 期刊:
- 影响因子:2.1
- 作者:Kobayashi, Masaki;Itagaki, Shirou;Iseki, Ken
- 通讯作者:Iseki, Ken
H+-Dependent Transport Mechanism of Nateglinide in the Brush-Border Membrane of the Rat Intestine
那格列奈在大鼠肠刷状缘膜中 H 依赖性转运机制
- DOI:
- 发表时间:2005
- 期刊:
- 影响因子:3.5
- 作者:S. Itagaki;Y. Saito;Sayaka Kubo;Yukio Otsuka;Yutaro Yamamoto;Masaki Kobayashi;T. Hirano;K. Iseki
- 通讯作者:K. Iseki
Transport mechanism for L-lactic acid in human myocytes using human prototypic embryonal rhabdomyosarcoma cell line (RD cells)
- DOI:10.1248/bpb.28.1197
- 发表时间:2005-07-01
- 期刊:
- 影响因子:2
- 作者:Kobayashi, M;Fujita, I;Iseki, K
- 通讯作者:Iseki, K
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ISEKI Ken其他文献
ISEKI Ken的其他文献
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{{ truncateString('ISEKI Ken', 18)}}的其他基金
The study of the repair mechanism by neuron and glial cell after central nervous system injury
中枢神经系统损伤后神经元和胶质细胞修复机制的研究
- 批准号:
24592729 - 财政年份:2012
- 资助金额:
$ 9.47万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The development of the side effect prediction of the anticancer agent which assumed intestinal tract immunity an index and the rating system
以肠道免疫为指标的抗癌剂副作用预测及评价体系的开发
- 批准号:
23659278 - 财政年份:2011
- 资助金额:
$ 9.47万 - 项目类别:
Grant-in-Aid for Challenging Exploratory Research
Neuronal and glial responses in the brain under hypoxic stress
缺氧应激下大脑神经元和神经胶质细胞的反应
- 批准号:
21592302 - 财政年份:2009
- 资助金额:
$ 9.47万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The study of repair mechanism by glial cells in injured brain
损伤脑胶质细胞修复机制的研究
- 批准号:
19592086 - 财政年份:2007
- 资助金额:
$ 9.47万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
A structure-relationship study of the transport mechanism of polyamine compounds across plasma membrane.
多胺化合物跨质膜转运机制的结构关系研究。
- 批准号:
07672414 - 财政年份:1995
- 资助金额:
$ 9.47万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
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利用英国食物垃圾生产 L-乳酸的可持续且具有成本效益的技术 (SCET-LAFOW)
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用聚左旋乳酸聚合物制成的生物可降解分流器治疗实验性动脉瘤的支架内皮化和动脉瘤闭塞的组织学评估
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Development of a New Poly-L-Lactic Acid Polymer Textile and Material Production Process Using Food Waste as Feedstock
以餐厨垃圾为原料的新型聚左旋乳酸聚合物纺织品及材料生产工艺的开发
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Development of a New Poly-L-Lactic Acid Polymer Textile and Material Production Process Using Food Waste as Feedstock
以餐厨垃圾为原料的新型聚左旋乳酸聚合物纺织品及材料生产工艺的开发
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Development of novel stent-grafts composed of bioresorbable Poly-L-lactic acid scaffold stents and decellularized porcine blood vessels by tissue-engineering technology
利用组织工程技术开发生物可吸收聚左旋乳酸支架支架和脱细胞猪血管组成的新型覆膜支架
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15K19926 - 财政年份:2015
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Water-induced Disintegrative Poly(L-lactic acid)(PLLA) Blends and Their Degradation Behavior
水诱导崩解性聚(L-乳酸)(PLLA)共混物及其降解行为
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PIEZOELECTRIC POLY-L-LACTIC ACID FABRIC AND ITS APPLICATION TO CONTROL OF HUMANOID ROBOT
压电聚左旋乳酸织物及其在仿人机器人控制中的应用
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15K13714 - 财政年份:2015
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Grant-in-Aid for Challenging Exploratory Research
Piezoelectric Poly(L-lactic acid) Nanofibres for Enhanced Neural Tissue Engineering
用于增强神经组织工程的压电聚(L-乳酸)纳米纤维
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Piezoelectric Poly(L-lactic acid) Nanofibres for Enhanced Neural Tissue Engineering
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