Effects of Fluvastatin and Its Major Metabolites on Low-Density Lipoprotein Oxidation and Cholesterol Esterification in Macrophages

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概要

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• We investigated effects of fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, and its major metabolites, M2 and M4, on CuSO4-induced low-density lipoprotein (LDL) oxidation and cholesteryl ester accumulation in mouse peritoneal macrophages. All the test compounds inhibited LDL oxidation, and M2 had the most potent effect comparable to vitamin E. When LDL was previously incubated with the test compounds in the presence of CuSO4, the pre-treatment resulted in a marked reduction of facilitated cholesteryl ester accumulation in macrophages. Supplementation of mevalonate did not overcome the inhibitory effects of fluvastatin and its metabolites on both LDL oxidation and facilitated cholesterol esterification. Pravastatin, another HMG-CoA reductase inhibitor, did not show any inhibitory effect. Consequently, these effects of fluvastatin and its metabolites are considered to be derived from their own unique chemical structures. Moreover, fluvastatin and M2 directly inhibited cholesterol esterification induced by oxidized LDL in macrophages, but pravastatin was also found to have a weak effect. As their inhibitory effects were overcome by addition of mevalonate, the direct inhibitory effect on cholesterol esterification would be a common property of HMG-CoA reductase inhibitors. The inhibitory effects of fluvastatin and its metabolites on both LDL oxidation and cholesterol esterification in macrophages may contribute to the antiatherogenic action in vivo.

• 社団法人 日本薬理学会の論文
• 2001-07-01

著者

• 斎藤 徹

  Faculty Of Pharmaceutical Sciences Kanazawa University

• Tanaka K

  Department Of Molecular Engineering Graduate School Of Engineering Kyoto University

• Suzuki T

  Drug Discovery Research Laboratory Sanwa Kagaku Kenkyusho Co. Ltd.

• Narita H

  Discovery Research Laboratory Tanabe Seiyaku Co. Ltd.

• Tanaka Ken-ichiro

  Faculty Of Pharmaceutical Sciences Okayama University

• 鈴木 徳治

  千葉大 薬

• Suzuki T

  Laboratory Of Biopharmaceutics Faculty Of Pharmaceutical Sciences Chiba University

• Saito T

  Research And Development Headquarters Hokurikit Seiyaku Co. Ltd.

• Saito Takako

  Research And Development Laboratories Maruho Co. Ltd.

• Suzuki Toshikazu

  Discovery Research Laboratory Tanabe Seiyaku Co. Ltd.

• Tanaka Katsuyuki

  Dept. Biol. Sci. Fac. Sci. Hiroshima Univ.

• Narita Hiroshi

  Discovery Research Laboratory Tanabe Seiyaku Co. Ltd.

• Narita Hiroshi

  Discovery Research Laboratory Tanabe Seiyaku Co. Ltd

• TANAKA Keiko

  Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd.

• YASUHARA Mikiko

  Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd.

• SUZUMURA Kuniharu

  Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd.

• Tanaka K

  Dept. Biol. Sci. Fac. Sci. Hiroshima Univ.

• Suzuki T

  Research Unit Of Pharmaceutics College Of Pharmacy Nihon University

• Sugihara T

  Faculty Of Pharmaceutical Sciences Tokushima Bunri University

• Saito T

  Research And Development Laboratories Maruho Co. Ltd.

• Yasuhara M

  Discovery Research Laboratory Tanabe Seiyaku Co. Ltd.

• Suzumura Kuniharu

  Discovery Research Laboratory Tanabe Seiyaku Co. Ltd.

• Suzumura Kuniharu

  Discovery Research Laboratory Tanabe Seiyaku Co. Ltd

• Narita Hiroshi

  Discovery Research Laboratories Tanabe Seiyaku Co. Ltd.

• Suzumura Kuniharu

  Faculty Of Pharmaceutical Sciences Chiba University

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