脂質異常症治療薬の副作用・薬物相互作用におけるモノカルボン酸トランスポータの役割

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  • 小林 正紀
    北海道大学大学院薬学研究院臨床薬剤学研究室

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タイトル別名
  • Role of Monocarboxylate Transporter in Statin-induced Cytotoxicity
  • シシツ イジョウショウ チリョウヤク ノ フクサヨウ ・ ヤクブツ ソウゴ サヨウ ニ オケル モノカルボンサン トランスポータ ノ ヤクワリ

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  Although exercise and drug therapy are important to prevent progression of arteriosclerotic disease, exercise leads to an increase in muscular disorder induced by HMG-CoA reductase inhibitors (statins). Elucidation of this mechanism is needed to prevent the occurrence of muscular disorders. Since exercise induces expression of monocarboxylate transporter (MCT) 4, we focused on the association between MCT4 function and statin-induced muscle injury. First, we examined the transport of L-lactate via MCT4 using MCT4 cRNA-injected Xenopus laevis oocytes. L-lactate uptake by MCT4-expressing oocytes was markedly reduced by alkalizing the buffer pH and saturated at higher L-lactate concentrations. On the other hand, AMP-activated protein kinase (AMPK) and protein kinase C (PKC) are activated by exercise. We next examined whether AMPK and PKC activation affects the expression and function of MCT4 in rat skeletal muscle and RD cells as an in vitro skeletal muscle model. AMPK and PKC activation increased MCT4 expression level and lactate efflux by MCT4. Finally, we examined the association between MCT4 function and statin-induced cytotoxicity. Statins inhibited transport of L-lactate via MCT4 in a concentration-dependent manner. Statin-induced cytotoxicity was associated with intracellular acidification and caspase-3/7 activation. On the other hand, bicarbonate suppressed statin-induced pH alteration, caspase activation, and morphological change. The results suggest that statin-induced muscle injury exacerbated by exercise is associated with intracellular acidification and that the effects of statins on L-lactate transport are mediated by MCT4.<br>

収録刊行物

  • 薬学雑誌

    薬学雑誌 135 (11), 1227-1233, 2015

    公益社団法人 日本薬学会

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