JP2009242374A - 肝線維化抑制剤 - Google Patents
肝線維化抑制剤 Download PDFInfo
- Publication number
- JP2009242374A JP2009242374A JP2008318593A JP2008318593A JP2009242374A JP 2009242374 A JP2009242374 A JP 2009242374A JP 2008318593 A JP2008318593 A JP 2008318593A JP 2008318593 A JP2008318593 A JP 2008318593A JP 2009242374 A JP2009242374 A JP 2009242374A
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- Prior art keywords
- pac
- hepatic stellate
- stellate cell
- hepatic
- liver fibrosis
- Prior art date
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Landscapes
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Non-Alcoholic Beverages (AREA)
- Pyrane Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
【解決手段】 プロアントシアニジン組成物を有効成分とする肝線維化抑制剤。
【選択図】 図5
Description
(i)4位炭素及び8位炭素の結合
(ii)4位炭素及び6位炭素の結合
(iii)4位炭素及び8位炭素の結合並びに2位炭素及び7位酸素の結合
(i)4位炭素及び8位炭素の結合
(ii)4位炭素及び6位炭素の結合
(iii)4位炭素及び8位炭素の結合並びに2位炭素及び7位酸素の結合
Proanthocyanidin BP 1 (Unspecified),
Proanthocyanidin RP 4 (C129 H106 O67),
Proanthocyanidin RP 3 (C136 H120 O70),
Proanthocyanidin CS 4 (C136 H120 O70),
Proanthocyanidin CS 3 (C127 H128 O69),
Proanthocyanidin CS 2 (C113 H110 O62),
Proanthocyanidin CS1 (C121 H118 O65),
Proanthocyanidin RP 2 (C120 H114 O64),
Proanthocyanidin RP 1 (C125 H130 O69),
Proanthocyanidin T4 (C128 H122 O65),
Proanthocyanidin T3 (C105 H102 O59),
Proanthocyanidin T2 (C67 H54 O29),
Proanthocyanidin T1 (C87 H72 O43),
4−(Benzylthio)proanthocyanidin A2 (C37 H30 O12 S),
Proanthocyanidin A7(C30 H24 O12),
Proanthocyanidin (C30 H24 O12),
Proanthocyanidin A5’(C30 H24 O12),
Proanthocyanidin A4 (C30 H24 O12),
Proanthocyanidin B6 (C37 H30 O16),
Proanthocyanidin B2 3,3’−O−gallate (C44 H34 O20),
Proanthocyanidin B4 (C30 H26 O12),
Proanthocyanidin A2 4α−bezylthioether (C37 H30 O12 S),
Proanthocyanidin A2 (C30 H24 O12),
Proanthocyanidin C1 (C45 H38 O18),
Proanthocyanidin B2 (C30 H26 O12),
Proanthocyanidin B (C31 H28 O12),
Methylated polymeric proanthocyanidin {(C29 H32 O10)x},
Proanthocyanidin B1 (C30 H26 O12),
Proanthocyanidin A (C31 H28 O12),
Proanthocyanidin C(C30 H26 O12),
Proanthocyanidin B5(C30 H26 O12),
Proanthocyanidin P−1 (Unspecified).
葉、皮、果実、茎、根等の全草部位に応じて、あらかじめ水洗、濾別などにより物理的に不純物を除く。あるいは、葉緑素、繊維素等、本発明のPAC以外の成分を溶媒で留去することもできる。この溶媒には、留去する対象により異なるが、クロロホルム、ヘキサン、アセトン等を用いることができる。生の素材は、そのまま粉砕しても乾燥後粉砕して、粉末状で次工程に供してもよいし、生素材からの搾汁液、抽出液を次工程に供してもよい。搾汁又は抽出液は、濃縮又は乾燥して粉末状で次工程に供してもよい。
前工程で得られた加工処理物は、次に溶媒抽出することができる。溶媒抽出には、下記の溶媒を適宜組み合わせて、必要に応じ多段抽出する。使用する抽出溶媒は特に制限されないが、水又は水と相溶性のある極性溶媒の使用が好適である。水と相溶性のある極性溶媒としては、メタノール、エタノール、プロパノール、ブタノールなどの炭素数1〜4の低級アルキルアルコール;エチレングリコール、ブチレングリコール、プロピレングリコール、グリセリンなどの多価アルコールなどを挙げることができる。アルコールとしては、安全性の観点から低級アルコール、特にメタノールやエタノールの使用が実際的である。他の有機溶媒としては、例えばアセトン、ジエチルエーテル、ジオキサン、アセトニトリル、酢酸エチルエステル、キシレン、クロロホルム、トルエン、ヘキサンなどを挙げることができる。水と極性溶媒の組み合わせを含め、これらの溶媒は、単独あるいは2種以上を組み合わせて使用してもよい。例えば、アセトンとエチルエーテルの混合溶媒、好ましくはアセトンとエチルエーテルの1 : 1(v/v)混合液の使用が可能である。一般的には、極性溶媒と水との混合溶媒の使用が望ましい。これらの含水溶媒としては、含水アルキルアルコール、より好ましくは含水メタノール、含水エタノールである。含水アルコール中のアルコール濃度は、5〜90容量%、好ましくは80〜90容量%、より好ましくは50〜90容量%である。アルコール以外の好ましい混合溶媒としては、水とアセトンの混液を挙げることができる。
PACは、上述のとおり、広く植物界から見いだされている。PACを含有することが報告されている下記に挙げる素材(試料1〜3)を入手し、PAC画分を調製した。
試料2:ブドウ種子抽出物(グラヴィノールTM:キッコーマン株式会社)
試料3:クロトン樹液(Sangre de Drago; Raintree Nutrition, Inc.)
ラビットアイブルーベリー種(Vaccinium virgatum Aiton)の生葉を、凍結乾燥(FTS System、Dura−Top MP&Dura−Dry MP)し、超遠心粉砕機(MRK&RETSCH、EM−1)で粉砕することで、ブルーベリー葉の凍結乾燥粉末を得た。この凍結乾燥粉末10gに100mlのヘキサンを加え、室温で30分間振盪抽出し、デカンテーションにより残渣を回収した。この抽出操作を3回繰り返し、ブルーベリー葉ヘキサン洗浄物を得た。
試料2〜3は、素材を直接入手して、100%メタノールで抽出を行い、減圧濃縮後、凍結乾燥した。その後、上記調製と同じように、セファデックスLH−20でPAC画分を調製した。
各起源から抽出された上記試料1〜3につき、PAC純度、組成及び平均重合度を調べた。以下に用いた解析方法と結果を示す。
下記文献の方法に従い、ポーター法を用いてPACの分析を行った。
・Porter L. J. et al.、“Phytochemistry”、1986年、第25巻、p.223−230
・Shoji T. et al.、“J. Agric. Food Chem.”、2006年、第54巻、p.884−892
精製画分をメタノールに溶解し、その200μlに5%(v/v)塩酸を含む1−ブタノール750μlと1%(w/v)硫酸鉄アンモニウムを含む2mol/L塩酸50μlを添加し、105℃で40分間反応させた。反応液を室温に戻し、540nmにおける吸光度を測定した。コントロールとしてプロシアニジンB2(Sigma社製)を用いた。
LC/MSを用いて上記ポーター法反応分解物の分析を実施した。もしブルーベリー葉から精製したPACであれば、アントシアニジンを検出するはずである。LC/MSに用いた装置及び条件は下記の通りである。
・装置:Shimadzu LC/MS−IT−TOF
・カラム:Atlantis T3、2.1mm I.D.×100mm、3μm(Waters製)、40℃
・移動相(溶出液):(A)5mMギ酸アンモニウムを含む0.5%(v/v)ギ酸
(B)アセトニトリル
・グラジエント:溶出液B 10%(0分)→40%(15分)→100%(15分)→100%(22.5分)
・移動相流速:0.25ml/分
・検出器1:フォトダイオードアレイ540nm
・検出器2:ESI−MS
(Positive−Ion Mode、インターフェイス電圧:4.5kV、
CDL温度200℃、ネブライズガス流量:1.5L/分、
ドライガス圧力:200kPa、ヒートブロック温度:200℃)
上記結果より、各植物由来調製物の主成分がPACであることが示された。次いでここでは、PACの構成単位、結合様式及び重合度を調べるために、Guyotらの方法(Guyot S. et al.、“J.Agric.Food Chem.”、2001年、第49巻、p.14−20参照)に基づきチオール開裂分析を行った。
平均重合度(mDP)=[ターミナルユニット+エクステンションユニット]/[ターミナルユニット]
ブルーベリー葉由来活性化合物PACを、メタノールで1mg/mlに調製し、50μlを取り、3.3%(v/v)塩酸メタノール50μlを加え、5%(v/v)トルエン−α−チオール100μlを加え、50℃で30分間反応させた後、反応液を5倍にメタノールで希釈し、HPLCに供した。HPLC条件を以下に示す。
・装置:Shimadzu Prominence LC−20A
・カラム:Atlantis T3,4.6mm I.D.×150mm,3μm(Waters製)、40℃
・移動相(溶出液):(A)0.05%(v/v)トリフルオロ酢酸
(B)アセトニトリル
・グラジエント:溶出液B 15%(0分)→25%(10分)→60%(40分)→100%(40分)→100%(50分)
・移動相流速:0.70ml/分
・検出器:UV280nm
上記反応物を同様にLC/MSに供し各検出ピークの同定を行った。分析条件は下記に示す。
・装置:Shimadzu LC/MS−IT−TOF
・カラム:Atlantis T3,2.1mm I.D.×100mm(Waters製)
・移動相(溶出液):(A)0.05%(v/v)トリフルオロ酢酸
(B)アセトニトリル
・グラジエント:溶出液B 15%(0分)→25%(10分)→60%(40分)→100%(40分)
・移動相流速:0.25ml/分
・検出器1:フォトダイオードアレイ280nm
・検出器2:ESI−MS
(Positive−Ion Mode、インターフェイス電圧:4.5kV、CDL温度200℃、ネブライズガス流量:1.5L/分、ドライガス圧力:200kPa、ヒートブロック温度:200℃)
mDP=[(ベンジルチオエーテル付加物×n)の総和+(遊離フラバン−3−オール×n)の総和]/[遊離フラバン−3−オールの総和]
(1)ブルーベリー葉由来のPACは平均重合度が11.2であり、エピカテキン組成比が高く、すべてプロシアニジンで構成されていた。加えて、Aタイプの結合を有しており、さらに未同定な側鎖も確認できた。
(2)ブドウ種子由来のものは平均重合度が14.4とブルーベリーより長く、ターミナルユニットはカテキンの組成比が高く、エクステンションはエピカテキンとエピカテキンガレートがおよそ1:1であった。Aタイプの結合様式やガレート以外の側鎖は確認されなかった。
(3)クロトン種樹液由来のものは平均重合度が8.3で、ガロカテキンとエピガロカテキンを確認した。そのプロデルフィニジン含量は約40%であった。
肝星細胞として、ヒト培養肝星細胞継代培養株(LI90;財団法人ヒューマンサイエンス振興財団より購入,カタログNo.,JCRB0160)を用い、肝線維化抑制機能を評価した。
(1)ブルーベリー葉由来BB−PACは、LI90細胞の増殖、及びPDGF−BB処理によるLI90細胞のDNA合成活性化をEGCG同様に強く抑制する。
(2)ブドウ種子由来のGL−PAC及びクロトン樹液由来のCL−PACにもブルーベリー葉由来のBB−PACと同等の抑制効果が認められる。
(3)カテキン、エピカテキン及びプロシアニジンB2のような単量体や二量体には、同様の抑制効果が殆ど認められない。
(4)ブルーベリー葉由来のBB−PACは、PDGF−BB処理によるERK及びAktのリン酸化を抑制する。
(5)BB−PACは、PDGF−BB処理したLI90細胞のアポトーシスを誘導する。
Claims (9)
- プロアントシアニジン組成物を有効成分とする肝線維化抑制剤。
- 前記プロアントシアニジン組成物は、
下記一般式(1)
[式(1)中、R1及びR3はそれぞれ独立に水素原子又は水酸基、R2は水酸基、R4は水素原子又は一価の有機基を、それぞれ示す。]
で表されるフラバン−3−オール骨格が、下記(i)、(ii)又は(iii)の結合様式で2以上互いに結合した構造を有する、請求項1記載の肝線維化抑制剤。
(i)4位炭素及び8位炭素の結合
(ii)4位炭素及び6位炭素の結合
(iii)4位炭素及び8位炭素の結合並びに2位炭素及び7位酸素の結合 - 前記プロアントシアニジンは天然物由来である、請求項1又は2記載の肝線維化抑制剤。
- プロアントシアニジン組成物を有効成分とする肝星細胞増殖抑制剤。
- 前記プロアントシアニジン組成物は、
下記一般式(1)
[式(1)中、R1及びR3はそれぞれ独立に水素原子又は水酸基、R2は水酸基、R4は水素原子又は一価の有機基を、それぞれ示す。]
で表されるフラバン−3−オール骨格が、下記(i)、(ii)又は(iii)の結合様式で2以上互いに結合した構造を有している、請求項4記載の肝星細胞増殖抑制剤。
(i)4位炭素及び8位炭素の結合
(ii)4位炭素及び6位炭素の結合
(iii)4位炭素及び8位炭素の結合並びに2位炭素及び7位酸素の結合 - 前記プロアントシアニジンは天然物由来である、請求項4又は5記載の肝星細胞増殖抑制剤。
- 肝星細胞アポトーシスに基づく、請求項4〜6のいずれか一項に記載の肝星細胞増殖抑制剤。
- 請求項1〜3のいずれか一項に記載の肝線維化抑制剤又は請求項4〜6のいずれか一項に記載の肝星細胞増殖抑制剤を含む、肝線維化を病因とする肝疾病の発症・進展抑制剤。
- 請求項1〜3のいずれか一項に記載の肝線維化抑制剤又は請求項4〜6のいずれか一項に記載の肝星細胞増殖抑制剤を含む、肝線維化抑制、肝星細胞増殖抑制、肝星細胞アポトーシス誘導、肝線維化を病因とする肝疾病の発症抑制、又は、肝線維化を病因とする肝疾病の進展抑制用の、機能性補助飲食物。
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