ᵝᘧ㸵 ㄽ ᩥ ෆ ᐜ せ ᪨ ሗ ࿌ ␒ ྕ எ 創 ➨ ４ ྕ Ꮫㄽᩥ㢟┠ Ặ ྡ ኳ㔝 㞝୍㑻 Pharmacological Research of a Farnesoid X Receptor Antagonist as an Antidyslipidemic Drug ෆᐜせ᪨ ඛ㐍ᅜ࠾ࡅࡿせṚᅉࡋ࡚ෙື⬦ᝈ㸦ᚰ➽᱾ሰࠊ⊃ᚰ࡞㸧ࡀᣲࡆࡽࢀࠊࡑࡢᇶ♏ᝈ࡛࠶ ࡿື⬦◳ᛶᝈࡀὀ┠ࡉࢀ࡚࠸ࡿࠋື⬦◳ࡢཎᅉ࡛࠶ࡿ⬡㉁␗ᖖࡣෙື⬦ᝈࡢ⊂❧ࡋࡓ༴㝤ᅉ Ꮚ࡛࠶ࡾࠊࡑࡢ⒪ண㜵ࡀῬᮃࡉࢀ࡚࠸ࡿࠋᮏ◊✲࡛ࡣࠊ᪤Ꮡ⸆↓࠸⾑୰⬡㉁ᨵၿ࣓࢝ࢽࢬ࣒ࢆ᭷ ࡋࠊࡘ⌧ᅾࡢ➨୍㑅ᢥ⸆࡛࠶ࡿࢫࢱࢳࣥ⣔⸆ࡢే⏝ࡶྍ⬟࡞᪂つ⬡㉁␗ᖖ⒪⸆ࡢฟࢆ┠ⓗ ࡋࠊࣇࣝࢿࢯࢻ X ཷᐜయ㸦FXR㸧ᣕᢠ⸆ࡢ⬡㉁␗ᖖᑐࡍࡿᨵၿస⏝ࢆ⸆⌮Ꮫⓗホ౯ࡋࡓࠋ ୍⯡⸆⌮◊✲㢖⏝ࡉࢀࡿࣛࢵࢺࡸ࣐࢘ࢫẚ࡚ࣄࢺ㢮ఝࡋࡓ⬡㉁௦ㅰㄪ⠇⣔ࢆ᭷ࡍࡿ࢝ࢽࢡ ࢨࣝࣔࣝࣔࢵࢺࢆ⏝࠸࡚ࠊFXR ᑐࡋ࡚ᙉຊࡘ㑅ᢥⓗ࡞ᣕᢠస⏝ࢆ᭷ࡍࡿ᪂つ FXR ᣕᢠ⸆ T3 ࠾ࡼࡧ T8 ࡢ⸆⌮ࣉࣟࣇࣝࢆ⢭ᰝࡋࡓࠋྜ≀ T3㸦0.3-10 mg/kg㸧ࡣࠊ㧗⬡⫫㣗㈇Ⲵ࢝ࢽࢡࢨࣝ ࣔࢹࣝ 1 㐌㛫ᢞࡍࡿࠊ⏝㔞౫Ꮡⓗୟࡘ᭷ព࡞⾑୰ LDL ࢥࣞࢫࢸ࣮ࣟࣝపୗస⏝⾑୰ HDL ୖ ᪼స⏝ࢆ♧ࡋࡓࠋࡇࡢࠊࢥࣞࢫࢸ࣮ࣟࣝ␗ࡢᚊ㏿㓝⣲࡛࠶ࡿࢥࣞࢫࢸ࣮ࣟࣝ 7DỈ㓟㓝⣲ࡢάᛶ ᣦᶆ࡛࠶ࡿ⾑୰ C4 ࡀቑຍࡋࠊ⣅୰ࡢ⫹Ồ㓟㔞ࡀቑຍࡋࡓࡇࡽࠊྜ≀ T3 ࡼࡿ⾑୰ LDL ࢥࣞࢫ ࢸ࣮ࣟࣝపୗస⏝ࡣࢥࣞࢫࢸ࣮ࣟࣝࡢ␗ἥ㉳ᅉࡍࡿࡇࡀ♧၀ࡉࢀࡓࠋ⮫ᗋୖࡢᑐ↷⸆࡞ࡾᚓ ࡿࢥࣞࢫࢸ࣮ࣟࣝ྾㜼ᐖࠊ⫹Ồ㓟྾╔ࠊ࠾ࡼࡧࢥࣞࢫࢸ࢚ࣜࣝࢫࢸࣝ㌿㏦㓝⣲㜼ᐖẚ㍑ࡋࡓ ሙྜࠊࡑࢀࡒࢀ HDL ቑຍస⏝ࠊLDL ᭱పୗ⋡ࠊLDL పୗస⏝࡛␗࡞ࡿ⸆⌮Ꮫⓗ≉ᛶࢆ♧ࡋࡓࠋ ྜ≀ T3㸦0.3, 3mg/kg㸧ᢞᚋࡢ㧗⬡⫫㣗㈇Ⲵ࢝ࢽࢡࢨࣝ⫢⮚ෆ⬡㉁௦ㅰኚࢆゎᯒࡋࡓ⤖ᯝࠊ⾑୰ LDL పୗస⏝ࡣࠊࢥࣞࢫࢸ࣮ࣟࣝ 7DỈ㓟㓝⣲άᛶࡼࡿࢥࣞࢫࢸ࣮ࣟࣝ␗ࡀᘬࡁ㔠࡞ࡾࠊ⫢ ⮚ࡢ⾑୰ LDL ྲྀࡾ㎸ࡳᶵᵓ࡛࠶ࡿ LDL ཷᐜయࡢቑຍ㉳ᅉࡍࡿࡇࡀ♧၀ࡉࢀࡓࠋࡲࡓࠊHDL ࡢ ᵓᡂࢱࣥࣃࢡ࡛࠶ࡿ࣏࣏ࣜࣉࣟࢸࣥ A-I ࡢቑຍഴྥࡀㄆࡵࡽࢀࠊ⾑୰ HDL ቑຍࡢ୍ᅉ⪃࠼ࡽࢀ ࡓࠋྜ≀ T8㸦30 mg/kg㸧ࢆࣔࣝࣔࢵࢺ 2 㐌㛫ᢞࡍࡿࠊ᭷ព࡞⾑୰ non-HDL ࢥࣞࢫࢸ࣮ࣟࣝ ࡢపୗࡀㄆࡵࡽࢀࡿࡶࠊࢫࢱࢳࣥ⣔⸆࡛࠶ࡿࢺࣝࣂࢫࢱࢳࣥ㸦30 mg/kg㸧ྠ⛬ᗘࡢ⾑୰ LDL ࢡࣜࣛࣥࢫቑຍస⏝ࡀほᐹࡉࢀࡓࠋྜ≀ T8㸦10 mg/kg㸧ࢺࣝࣂࢫࢱࢳࣥ㸦10 mg/kg㸧ࢆ 1 㐌㛫ే⏝ᢞࡋࡓࡇࢁࠊࡑࢀࡒࢀࡢ༢ẚ㍑ࡋࠊ┦ຍⓗ࡞⾑୰ non-HDL ࢥࣞࢫࢸ࣮ࣟࣝపୗస ⏝ࡀ☜ㄆࡉࢀࡓࠋ ௨ୖࡢᡂ⦼ࡽࠊFXR ᣕᢠ⸆ࡣࠊࢥࣞࢫࢸ࣮ࣟࣝ␗ಁ㐍ࢆ㉳ᅉࡍࡿ᪂つ࡞࣓࢝ࢽࢬ࣒ࢆ᭷ࡍࡿ⸆ ࡛࠶ࡾࠊ➨୍㑅ᢥ⸆࡛࠶ࡿࢫࢱࢳࣥ⣔⸆ࡢే⏝ࡶྍ⬟࡞⸆࡛࠶ࡿࡇࠊࡲࡓࢥࣞࢫࢸ࣮ࣟࣝ྾ 㜼ᐖࠊ⫹Ồ㓟྾╔ࠊ࠾ࡼࡧࢥࣞࢫࢸ࢚ࣜࣝࢫࢸࣝ㌿㏦㓝⣲㜼ᐖࡣ␗࡞ࡿ⸆⌮Ꮫⓗ≉ᛶࢆ᭷ࡍ ࡿ⸆࡛࠶ࡿࡇ♧၀ࡉࢀࠊFXR ᣕᢠ⸆ࡀ᪂つ⬡㉁␗ᖖ⒪⸆ᡂࡾᚓࡿࡇࡀ♧၀ࡉࢀࡓࠋ
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