Effect of the Hypocholesterolemic Agent YM-16638 on Cholesterol Biosynthesis Activity and Apolipoprotein B Secretion in HepG2 and Monkey Liver

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Author(s)

Abstract

YM-16638 ([[5-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl]thio]-1, 3, 4-thiadiazol-2-yl]thio] acetic acid) showed a strong hypocholesterolemic effect in humans and monkeys. To clarify the mechanism of this hypocholesterolemic effect, the action of YM-16638 on cholesterol biosynthesis in the cultured human hepatoma cell line HepG2 and cynomolgus monkey liver was examined. Cholesterol biosynthesis activity derived from [<SUP>14</SUP>C]acetic acid, [<SUP>3</SUP>H/<SUP>14</SUP>C]mevalonic acid or [<SUP>14</SUP>C]isopentenyl pyrophosphate substrates was significantly decreased, but not that from [<SUP>3</SUP>H]farnesyl pyrophosphate or [<SUP>3</SUP>H]squalene substrates in HepG2 cells treated with YM-16638. Simultaneously, treatment of these cells with YM-16638 changed neither the rate of apolipoprotein B synthesis from [<SUP>35</SUP>S]methionine nor its secretion. In addition, the activities of hepatic cholesterol biosynthesis enzymes HMG-CoA reductase, mevalonate kinase (MK), isopentenyl pyrophosphate isomerase (IPPI), farnesyl pyrophosphate synthase (FPPS), squalene synthase and squalene epoxidase were measured in monkeys fed a diet supplemented with YM-16638. Among these enzymes, MK, IPPI and FPPS activities in the YM-16638-treated group significantly decreased by 38%, 56% and 30%, respectively, when compared to those from control animals receiving no drug treatment. These results indicate that YM-16638 has the characteristics of a cholesterol biosynthesis inhibitor.

Journal

  • The Japanese Journal of Pharmacology

    The Japanese Journal of Pharmacology 79(1), 75-82, 1999-01

    The Japanese Pharmacological Society

References:  29

Codes

  • NII Article ID (NAID)
    10008194205
  • NII NACSIS-CAT ID (NCID)
    AA00691188
  • Text Lang
    ENG
  • Article Type
    ART
  • ISSN
    00215198
  • NDL Article ID
    4636942
  • NDL Source Classification
    ZS51(科学技術--薬学)
  • NDL Call No.
    Z53-D199
  • Data Source
    CJP  NDL  J-STAGE 
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