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

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 1 microM potently inhibited the incorporation of [3H]acetate into cholesterol (84%) without affecting that from [3H]mevalonolactone. Under these conditions, MK-733 reduced the incorporation of L-[14C]tyrosine into ubiquinone slightly (14%), although it did not suppress that from [3H] acetate. The incorporation of [3H]acetate into dolichol was slightly reduced by MK-733. On the contrary, the incorporation of [3H]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 10 microM.