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Research Article Pharmacokinetics, Pharmacodynamics and Drug Transport and Metabolism| Volume 105, ISSUE 4, P1544-1549, April 01, 2016

Involvement of Monocarboxylate Transporter 4 Expression in Statin-Induced Cytotoxicity

  • Yurika Kikutani
    Affiliations
    Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
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  • Masaki Kobayashi
    Affiliations
    Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
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  • Toru Konishi
    Affiliations
    Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
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  • Shotaro Sasaki
    Affiliations
    Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
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  • Katsuya Narumi
    Affiliations
    Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
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  • Ayako Furugen
    Affiliations
    Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
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  • Natsuko Takahashi
    Affiliations
    Hokkaido Pharmaceutical University School of Pharmacy, Sapporo 006-8590, Japan
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  • Ken Iseki
    Correspondence
    Correspondence to: Ken Iseki (Telephone/Fax: +81-11-706-3770).
    Affiliations
    Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan

    Department of Pharmacy, Hokkaido University Hospital, Sapporo 060-8648, Japan
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Published:February 27, 2016DOI:https://doi.org/10.1016/j.xphs.2016.01.014

      Abstract

      Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are the most widely used cholesterol-lowering agents for prevention of obstructive cardiovascular events. However, statins can cause a variety of skeletal muscle problems, and exercise leads to an increase in statin-induced muscle injury. Exercise induces the protein content of monocarboxylate transporter 4 (MCT4), which is expressed strongly in skeletal muscle and is thought to play a major role in the transport of metabolically important monocarboxylates such as l-lactate. We previously reported that α-cyano-4-hydroxycinnamate, an MCT4 inhibitor, increased the inhibition of growth of RD cells, a prototypic embryonal rhabdomyosarcoma cell line (an RD cell line), as a model of in vitro skeletal muscle, induced by a statin. However, it is unclear whether statin-induced RD cell cytotoxicity is associated with MCT4 expression. We, therefore, examined the relationship between statin-induced cytotoxicity and MCT4 expression in RD cells. Atorvastatin reduced the number of viable cells and upregulated MCT4, but not MCT1, mRNA level in a concentration-dependent manner. MCT4 knockdown suppressed atorvastatin-, simvastatin-, and fluvastatin-induced reduction of cell viability and apoptosis compared with negative control–treated cells. In this study, we demonstrated that MCT4 expression is associated with statin-induced cytotoxicity.

      Keywords

      Abbreviations used:

      MCT4 (monocarboxylate transporter 4), AMPK (AMP-activated protein kinase), PKC (protein kinase C), MTT (3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyl tetrazolium bromide), MRP (multidrug resistance–associated protein)
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