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2006 Fiscal Year Final Research Report Summary

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

Research Project

Project/Area Number 16390155
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Applied pharmacology
Research InstitutionHokkaido University

Principal Investigator

ISEKI Ken  Hokkaido University, Faculty of Pharmaceutical Sciences, Professor, 大学院薬学研究院, 教授 (40203062)

Co-Investigator(Kenkyū-buntansha) HIRANO Takeshi  Hokkaido University, Hokkaido University Hospital, Lecture, 病院・講師 (00322826)
Project Period (FY) 2004 – 2006
KeywordsMCT4 / L-lactic acid / statins / rhabdmyolysis / transport / apoptosis / intracellular acidification / drug-drug interaction
Research Abstract

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

  • Research Products

    (8 results)

All 2007 2006 2005 2004 Other

All Journal Article (8 results)

  • [Journal Article] Preventive effects of bicarbonate on cerivastatin-induced apoptosis.2007

    • Author(s)
      Masaki Kobayashi
    • Journal Title

      Int. J. Pharm. (in press)

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Inhibitory effects of statins on human monocarboxylate transporter 4.2006

    • Author(s)
      Masaki Kobayashi
    • Journal Title

      Int. J. Pharm. 317(1)

      Pages: 19-25

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Inhibitory effects of statins on human monocarboxylate transporter 4.2006

    • Author(s)
      Masaki Kobayashi
    • Journal Title

      Int J Pharm. 317(1)

      Pages: 19-25

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Transport mechanism for L-lactic acid in human myocytes using human prototypic embryonal rhabdomyosarcoma cell line (RD cells).2005

    • Author(s)
      Masaki Kobayashi
    • Journal Title

      Biol. Pharm. Bull. 28(7)

      Pages: 1197-1201

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Transport mechanism for L-lactic acid in human myocytes using human prototypic embryonal rhabdomyosarcoma cell line (RD cells).2005

    • Author(s)
      Masaki Kobayashi
    • Journal Title

      Biol Pharm Bull. 28(7)

      Pages: 1197-1201

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Mechanism of L-lactic acid transport in L6 skeletal muscle cells.2004

    • Author(s)
      Masaki Kobayashi
    • Journal Title

      Drug Metab. Pharmacokinet 19(5)

      Pages: 363-368

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Mechanism of L-lactic acid transport in L6 skeletal muscle cells.2004

    • Author(s)
      Masaki Kobayashi
    • Journal Title

      Drug Metab.Phannacokinet. 19(5)

      Pages: 363-368

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Preventive effects of bicarbonate on cerivastatin-induced apoptosis

    • Author(s)
      Masaki Kobayashi
    • Journal Title

      Int J Pharm. (in press)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2008-05-27  

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