Effects of simvastatin (MK-733) on branched pathway of mevalonate.

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概要

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• The effects of simvastatin (MK-733), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, on the branched pathway of mevalonate metabolism were studied in Hep G2 cells. The synthesis of cholesterol, ubiquinone and dolichol were examined using various radiolabeled precursors. The effect on DNA synthesis was also determined. MK-733 at a concentration of 1μM potently inhibited the incorporation of [<SUP>3</SUP>H]acetate into cholesterol (84%) without affecting that from [<SUP>3</SUP>H]mevalonolactone. Under these conditions, MK-733 reduced the incorporation of L-[<SUP>14</SUP>C]tyrosine into ubiquinone slightly (14%), although it did not suppress that from [<SUP>3</SUP>H]acetate. The incorporation of [<SUP>3</SUP>H]acetate into dolichol was slightly reduced by MK-733. On the contrary, the incorporation of [<SUP>3</SUP>H]mevalonolactone into ubiquinone and dolichol was increased by MK-733. This apparent increase in incorporation was thought to be largely due to the higher specific radioactivity of the intracellular pool of mevalonate. The present study demonstrated that MK-733 slightly suppressed the synthesis of ubiquinone and dolichol in Hep G2 cells. However, the extent of their reduction was far less than the effect on cholesterol synthesis, suggesting that there were differences in substrate affinity between the enzymes participating in the cholesterol synthetic pathway and those in the ubiquinone or dolichol synthetic pathway. Furthermore, MK-733 did not affect DNA synthesis even at a concentration of 10μM.

• 公益社団法人 日本薬理学会の論文

著者

• Hidaka Yusuke

  Central Research Laboratories Banyu Pharmaceutical Co. Ltd.

• KAMEI Toshio

  Central Research Laboratories, Banyu Pharmaceutical Co., Ltd.

• ISHIDA Fumiaki

  Central Research Laboratories, Banyu Pharmaceutical Co., Ltd.

• NAGATA Yasufumi

  Central Research Laboratories, Banyu Pharmaceutical Co., Ltd.

関連論文

• Environmental Differences of a Pyridine Derivative (AU-1421)-Access Sites between (H^+, K^+)-ATPase and (Na^+, K^+)-ATPase
• Effect of simvastatin (MK-733) on sterol and bile acid excretion in rabbits.
• Preventive effect of MK-733 (simvastatin), an inhibitor of HMG-CoA reductase, on hypercholesterolemia and atherosclerosis induced by cholesterol feeding in rabbits.
• Effects of simvastatin (MK-733) on branched pathway of mevalonate.

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