YM116, 2-(lH-Imidazol-4-ylmethyl)-9H-carbazole, Decreases Adrenal Androgen Synthesis by Inhibiting C17-20 Lyase Activity in NCI-H295 Human Adrenocortical Carcinoma Cells

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著者

    • Kudoh Masafumi KUDOH Masafumi
    • Metabolic Diseases Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
    • SUSAKI Yoko
    • Metabolic Diseases Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
    • NANYA Taiki
    • Metabolic Diseases Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
    • NAKAHARA Takahito
    • Metabolic Diseases Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
    • ISHIKAWA Hiroko
    • Metabolic Diseases Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
    • FUJIKURA Takashi
    • Metabolic Diseases Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
    • AKAZA Hideyuki
    • Department of Urology, Institute of Clinical Medicine, University of Tsukuba
    • SHIKAMA Hisataka
    • Metabolic Diseases Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.

抄録

The concentrations of androstenedione and dehydroepiandrosterone, products of C17-20 lyase, in the medium after a 6-hr incubation of NCI-H295 cells were decreased by YM116 (2-(1<I>H</I>-imidazol4-ylmethyl)-9<I>H</I>-carbazole) (IC<SUB>50</SUB>: 3.6 and 2.1 nM) and ketoconazole (IC<SUB>50</SUB>: 54.9 and 54.2 nM). 17αHydroxyprogesterone, a product of 17α-hydroxylase, was increased by YM116 (1 - 30 nM) and by ketoconazole (10 - 300 nM) and then was decreased at higher concentrations of both agents (IC<SUB>50</SUB>: 180 nM for YM116, 906 nM for ketoconazole), indicating that YM116 and ketoconazole were 50- and 16.5-fold more specific inhibitors of C17-20 lyase, respectively, than 17α-hydroxylase. Compatible with these findings, progesterone, a substrate of 17α-hydroxylase, was increased by these agents. Cortisol production was inhibited by YM116 and ketoconazole (IC<SUB>50</SUB>: 50.4 and 80.9 nM, respectively). YM116 was a 14-fold more potent inhibitor of androstenedione production than cortisol production, whereas ketoconazole was a nonselective inhibitor of the production of both steroids. YM116 and ketoconazole inhibited the C17-20 lyase activity in human testicular microsomes (IC<SUB>50</SUB>: 4.2 and 17 nM, respectively). These results demonstrate that YM116 reduces the synthesis of adrenal androgens by preferentially inhibiting C17-20 lyase activity.

収録刊行物

  • The Japanese journal of pharmacology

    The Japanese journal of pharmacology 79(2), 213-220, 1999-02-01

    公益社団法人 日本薬理学会

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各種コード

  • NII論文ID(NAID)
    10008682403
  • NII書誌ID(NCID)
    AA00691188
  • 本文言語コード
    ENG
  • 資料種別
    REV
  • ISSN
    00215198
  • NDL 記事登録ID
    4663544
  • NDL 雑誌分類
    ZS51(科学技術--薬学)
  • NDL 請求記号
    Z53-D199
  • データ提供元
    CJP書誌  NDL  J-STAGE 
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