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

• Goto Shoichiro

  Cardiovascular & Atherosclerosis Research Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.

• Shimokawa Teruhiko

抄録

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 [¹⁴C]acetic acid, [³H/¹⁴C]mevalonic acid or [¹⁴C]isopentenyl pyrophosphate substrates was significantly decreased, but not that from [³H]farnesyl pyrophosphate or [³H]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 [³⁵S]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.

収録刊行物

• Jpn.J.Pharmacol.

  Jpn.J.Pharmacol. 79 (1), 75-82, 1999

  公益社団法人 日本薬理学会

キーワード

• Cholesterol biosynthesis enzyme
• Cynomolgus monkey
• HepG2 cell
• Hypocholesterolemic effect
• YM-16638

詳細情報

• CRID: 1390001204284560768
• NII論文ID: 10008194205
• NII書誌ID: AA00691188
• DOI: 10.1254/jjp.79.75
• COI: 1:CAS:528:DyaK1MXns1ynuw%3D%3D
• ISSN: 13473506
• ISSN: 00215198
• NDL書誌ID: 4636942
• PubMed: 10082320
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I4636942
• Web Site: https://api.elsevier.com/content/article/PII:S0021519819309916?httpAccept=text/xml
• Web Site: https://api.elsevier.com/content/article/PII:S0021519819309916?httpAccept=text/plain
• Web Site: https://www.jstage.jst.go.jp/article/jjp/79/1/79_1_75/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/1999133494
• 本文言語コード: en
• データソース種別:
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  • NDL
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