JP4536823B2 - アロマターゼ阻害剤 - Google Patents
アロマターゼ阻害剤 Download PDFInfo
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- JP4536823B2 JP4536823B2 JP2009257749A JP2009257749A JP4536823B2 JP 4536823 B2 JP4536823 B2 JP 4536823B2 JP 2009257749 A JP2009257749 A JP 2009257749A JP 2009257749 A JP2009257749 A JP 2009257749A JP 4536823 B2 JP4536823 B2 JP 4536823B2
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- aromatase
- dried
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- tea
- testosterone
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Description
従って、安全で副作用のない天然素材で治療や予防効果が期待できる医薬品又は健康食品の開発が望まれている。更に、そのような素材を基に、新薬開発のための新たな先導化合物の発見も期待されている。
非特許文献5)。
男性では加齢と共に男性ホルモンから女性ホルモンへの変換率が増加することが報告されている(非特許文献7)。また、性腺機能低下又は男性ホルモン欠乏症の男性に対してアロマターゼ阻害剤を投与することで、血中テストステロン値が回復又は増加することが報告されている(非特許文献8、特許文献1)。
Chen S, Aromatase and breast cancer, Frontiers in Bioscience,3;d922−933,1998. Simpson ER and Dowsett M., Aromatase and its inhibitors:significance for breast cancer therapy, Recent Prog Horm Res.,57;317−38,2002. 磯村八州男、岡田稔、アロマターゼ阻害薬の研究開発動向,ファルマシア,30巻,754−758,1994. Dietmar G, Gerhard S.,Aromatase inhibitors from Urtica dioca Roots,Planta Med.,61;138−140,1995. Kim DS,Jeong,HJ,et al.,Aromatase and sulfatase inhibitos from Lepiota americana, Planta Med.,66;78−79,2000. Elizabeth TE,Dudley W,Usha M,et al.,Suppression of aromatase (estrogen synthetase) by red wine phytochemicals, Breast Cancer Research and Treatment, 67;133−146,2001. Filleur F,Le bail JC,et al.,Antiproliferative, anti−aromatase, anti−17β−HSD and antioxidant activities of lignans isolated from Myritica argentea, Planta Med.,67;700−704,2001. Minami T,Iwamoto M,Ohtus H,et al.,Aromatase inhibitiory activities of standishinal and the diterpenoid from the bark of Thuja standishii, Planta Med.,68;742−745,2002. Lamberts SWJ,et al., The endocrinology of aging, Science,278;419−424,1997. 伊藤直樹、塚本泰司、男性更年期の概念、医学のあゆみ、205巻;380―383,2003. 岩本晃明等、日本人成人男性の総テストステロン、遊離テストステロンの基準値設定, 日泌尿会誌、95巻; 751―760,2004. 碓井 亜、松原昭郎、男性ホルモン補充療法、医学のあゆみ、205巻;407―410,2003. 佐藤嘉一、丹田均、男性ホルモン補充療法の適応と問題点、総合臨床、53巻;451―457,2004. Braunstein GD, Aromatase and gynecomastia, Endocrione−Related Cancer, 6;315−324,1999. Leder BZ,et al., Effects of aromatase inhibitior in elderly men with low or borderline−low serum testosterone levels, J Clin Endocrinol Metab.,89;1174−1180,2004. de Boer H,et al., Letrozole normalizes serum testosterone in severely abese men with hypogonadotropic hypogonadism, Diabetes Obes Metab,7;211−215,2005. Raman JD,et al., Aromatase inhibitors for male infertility, The Journal of Urology, 167;624−629,2002. 河源、松田公志、メタボリックシンドロームとテストステロンおよび男性更年期障害、最新医学、61巻;227―233,2006. Lunenfeld B., Testosterone deficiency and the metabolic syndrome, The Aging Male, 10;53−56,2007. Seidell J,Bjorntorp P,et al., Visceral fat accumulation is positively associated with insulin, glucose and C−peptide levels but negatively with testosterone levels, Metabolism, 39;897−901,1990. Kyle UG,Genton L,et al., Age−related differences in fat−free mass, skeletal muscle, body cell mass and fat mass between 18 and 94 years, Eur J Clin Nutr.,55;663−672,2001. Bjorntorp P, Adipose tissue distribution and function,International Journal of Obesity,15;67−81,1991. Grooren L, Visceral obesity, the metabolic syndrome, androgens and estrogens, The Aging Male, 9;75−79,2006. Grooren L,Toorians AW, Significance of estrogens in male (patho)physiology, Ann Endocrinol., 64;126−135,2003. Cohen PG, The hypogonadal−obesity cycle: role of aromatase in modulating the testosterone−estradiolshunt−a major factor in the genesis of morbid obesity, Med Hypotheses, 52;49−51,1999. Cohen PG, Holbrook JM, Other pathways to the manifestations of the Metabolic Syndrome in males, Obesity Research, 12;1536,2004. Rebuffe−Scrive M, Marin P, Bjorntorp P, Effect of testosterone on abdominal adipose tissue in men, Int J Obes.,15;791−795,1991. Allan CA,Strauss BJ,et al., Testosterone therapy prevents gain in visceral adipose tissue and loss of skeletal muscle in non−obese aging men, J Clin Endocrinol Metab. ,2007 Oct 16,[Epub ahead of print]. Schroeder ET,Zheng L,et al.,Effects of androgen therapy on adipose tissue and metabolism in older men, J Clin Endocrinol Metab.,89;4863−4872,2004. Syder PJ,et al.,Effects of testosterone replacement in hypogonadal men, J Clin Endocrinol Metab.,65;2670−2677,2000.
ゲン合成を抑制するアロマターゼ阻害剤が上記乳癌のようなエストロゲン依存性疾患に対する有効な治療薬として注目されている。しかしながら、我が国においては臨床使用が承認されているアロマターゼ阻害剤は僅かで、かつ様々な副作用のために、その使用は制限されている。
1.紅景天、夏枯草、甘茶、マリアアザミ、ジャスミン茶、ボクソク、甜茶、旱連草、楊梅皮、フランス海岸松、檳榔、アスパラガス、漏芦、良姜、ルイボス茶、大黄、プーアル茶、緑茶、オウゴン、西洋オトギリソウ、甘草、千里光、ウィンターグリーン、訶子、野梧桐、何首烏、インヨウカク、ガラナ、桜皮、艾葉、地黄、山茱萸、細辛、桂皮、芍薬、松葉、アムラ或いは抽出物からなる群より1種又は2種以上選択される生薬の抽出物を含有することを特徴とするアロマターゼ阻害剤である。
2.1に記載のアロマターゼ阻害剤を含有することを特徴とする性ホルモン依存性疾患の治療及び/又は予防剤である。
梧桐、何首烏、インヨウカク、ガラナ、桜皮、艾葉、地黄、山茱萸、細辛、桂皮、芍薬、松葉、アムラの抽出物がアロマターゼ活性を阻害するという知見を得た。これらの生薬についての詳細は次の通りである。
(2)夏枯草(カゴソウ)はシソ科(Labiaceae)のウツボグサ(Prunellavulgaris L.var.lilacina Nak.)の果穂を乾燥したものである。
(3)甘茶(アマチャ)はユキノシタ科(Saxifragaceae)の落葉低木ガクアジサイの変種であるアマチャ(Hydrangea macrophylla var. thunbergii)の若い葉を蒸して揉み、乾燥させものである。
(4)マリアアザミはキク科(Asteraceae)のオオアザミ(Silybum
marianum L.、別名Carduus marianus L.)の痩果を乾燥したものである。
(5)ジャスミン茶は緑茶とジャスミン(Jasminum sambac (L.) Ait.)の花弁を混合し、乾燥したものである。
(6)ボクソクはブナ科(Fagaceae)のクスギ(Querus acutissima)またはその他近縁植物の樹皮を乾燥したものである。
(7)甜茶(テンチャ)はユキノシタ科(Saxifragaceae)のロウレンシュウキュウ(Hydrangea strigosa Rehd.)或いはヤクシマアジサイ(Hydrangea umbellate Rehd.)の若葉を乾燥させたものである。
(8)旱連草(カンレンソウ)はキク科(Compositae)のタカサブロウ(Eclipta prostrata)の全草を乾燥したものである。
(9)楊梅皮(ヨウバイヒ)はヤマモモ科(Myricaceae)の山桃(Myrica rubra Sieb. et Zucc.)の樹皮を乾燥したものである。
(10)フランス海岸松はマツ科(Pinaceae)のPinus pinasterあるいはP.maritimaの樹皮を乾燥したものである。
(11)檳榔(ビンロウ)はヤシ科(Arecaceae)の植物ビンロウ(Arecacatechu L.)の種子を乾燥したものである。
(12)アスパラガスはユリ科(Liliaceae)のオランダキジカクシ(Asparagus offcinalis L.)の根茎また根を乾燥したものである。
(13)漏芦(ロウロ)はキク科(Compositae)の祈州漏芦(Rhaponticum uniflorum DC.)オオルリヒゴタイ(Echinops latifolius Tausch)の根を乾燥させたものである。
(14)良姜(リョウキョウ)はショウガ科(Zingiberaceae)の高良姜(Alpinia officinarum Hance)の根茎を乾燥したものである。
(15)ルイボス茶マメ科(Leguminosae)のAspalathus linearisの針葉樹様の葉を乾燥したものである。
(16)大黄(ダイオウ)はタデ科(Polygonaceae)の掌葉大黄(Rheum palmatum L.)、唐古特大黄(R.tanguticum Maxim.ex Rgl.)、葯用大黄(R.officinale Baillon)又はR.coreanum Nakaiまたはそれらの種間の雑種の根茎を乾燥させたものである。
(17)プーアル茶は加熱によって酸化発酵を止めた緑茶を、コウジカビ(Aspergillus)で発酵させ、乾燥したものである。
(18)緑茶(リョクチャ)はツバキ科(Theaceae)の茶の木(Camell
ia sinensis Kunt)の葉を乾燥したものである。
(19)オウゴンはシソ科(Labiatae)のコガネバナ(Scutellaria baicalensis Georgi)の根を乾燥させたものである。
(20)西洋オトギリソウは金絲桃科(Hypericaceae)のセイヨウオトギリソウ(Hypericum perforatum L.)の地上部を乾燥したものである。
(21)甘草(カンゾウ)はマメ科(Leguminosae)のウラルカンゾウ(Glycyrrhiza uralensis Fisch.)又は西北甘草(G.glabra L.)の根とストロンを乾燥させたものである。
(22)千里光(センリコウ)はキク科(Compositae)のタイキンギク(Senecio scandens Buch.−Ham.)の全草を乾燥したものである。
(23)ウィンターグリーンはツツジ科(Ericaceae)のGaultheria procumbensの葉を乾燥したものである。
(24)訶子(カシ)はシクンシ科(Combretaceae)のTerminalia chebula Retz.の成熟した果実を乾燥したものである。
(25)野梧桐(ヤゴトウ)はトウダイグサ科(Euphorbiaceae)の赤芽槲(Mallotus japonicus)の樹皮を乾燥したものである。
(26)何首烏(カシュウ)はタデ科(Polygonaceae)のツルドクダミ(Polygonum multiflorum Thunberg)の塊根を乾燥したものである。
(27)インヨウカクはメギ科(Berberidaceae)のEpimedium
pubescens Maximowicz、E.brevicornum Maximowicz、E. wushanense T.S.Ying、ホザキイカリソウ(E.sagittatum Maximowicz)、キバナイカリソウ(E.koreanum Nakai)、イカリソウ(E.gradiflorum Morr.)又はトキワイカリソウ(E.sempervirens Nakai)の茎と葉を乾燥したものである。
(28)ガラナはムクロジ科(Sapindaceae)のPaullina cupana H.B.Kの種子を乾燥したものである。
(29)桜皮(オウヒ)はバラ科(Rosaceae)の植物ヤマザクラ(Prunus jamasakura Sieb.ex Koidz.)又は同属近縁植物の樹皮を乾燥したものである。
(30)艾葉(ガイヨウ)はキク科(Compositae)のヨモギ(Artemisia princeps Pamp.)又はヤマヨモギ(A. montana Pamp.)の全草又は葉を乾燥したものである。
(31)地黄(ジオウ)はゴマノハグサ科(Scrophulariaceae)のアカヤジオウ(Rehmannia glutinosa Liboschitz var.purpurea Makino)又はR.glutinosa Liboschitzの根を乾燥したものである。
(32)山茱萸(サンシュユ)はミズキ科(Cornaceae)のサンシュユ(Cornus officinalis Siebold et Zuccarini)の偽果の果肉を乾燥したものである。
(33)細辛(サイシン)はウマノスズクサ科(Aristolochiaceae)のウスバサイシン(Asiasarum sieboldii Miq.)又はケイリンサイシン(A.heterotropoides F.Schm.var.mandshuricum F.Maekawa)の根及び根茎を乾燥したものである。
(34)桂皮(ケイヒ)はクスノキ科(Lauraceae)の桂樹(Cinnamomum cassia Blume)の樹皮を乾燥したものである。
(35)芍薬(シャクヤク)はボタン科(Paeoniaceae)のシャクヤク(P
aeonia lactiflora Pall.)の根を乾燥したものである。
(36)松葉(マツバ)はマツ科(Pinaceae)赤松(Pinus densiflora Sieb.et Zucc.)または黒松(P.thunbergii Parl.)の葉を乾燥したものである。
(37)アムラはトウダイグサ(Euphorbiaceae)科のEmblica officinalis Gaertnの果実を乾燥したものである。
抽出物としては、これら各種の生薬から溶媒を用いて直接抽出することで得られるものの他、圧搾処理を施した後に得られる圧搾液及び/又は残渣に溶媒を加えて抽出することで得られるものも、本発明における抽出物の定義の範囲に含まれる。
実施例1〔生薬抽出方法(1)〕
夏枯草(果穂)、甘茶(葉)、ジャスミン茶(葉、花)、ボクソク(樹皮)、甜茶(葉)、旱連草(全草)、楊梅皮(樹皮)、フランス海岸松(樹皮)、檳榔(種子)、漏芦(根)、良姜(根茎)、ルイボス茶(葉)、大黄(根)、プーアル茶(葉)、緑茶(葉)、オウゴン(根茎)、甘草(根)、千里光(全草)、ウィンターグリーン(葉)、訶子(果実)、野梧桐(皮)、何首烏(塊根)、インヨウカク(葉)、桜皮(皮)、艾葉(全草)、地黄(根)、山茱萸(果肉)、細辛(根)、桂皮(皮)、芍薬(根)、松葉(葉)の各乾燥物100gに各300Lの精製水を加え、80℃にて1時間加温還流で2回抽出し、濾過した抽出液を定法により凍結乾燥した。その結果、乾燥固形分としてそれぞれ18.5g、31.0g、27.3g、31.2g、13.8g、17.6g、20.4g、23.6g、17.8g、21.5g、22.0g、19.8g、35.5g、14.9g、12.7g、32.1g、33.7g、14.3g、15.1g、21.4g、24.3g、35.3g、15.2g、21.1g、12.3g、33.6g、30.8g、29.3g、25.1g22.1g、15.0gを得た。
アスパラガス(根茎、根)乾燥物100gに300Lの30%エタノール/精製水を、ガラナ(種子)乾燥物100gに300Lの35%エタノール/精製水を、紅景天(地下部)乾燥物100gに300Lの50%エタノール/精製水を、西洋オトギリソウ(地上部)乾燥物及びアムラ(果実)乾燥物各100gに各300Lの60%エタノール/精製水を、マリアアザミ(果皮)乾燥物100gに300Lの80%エタノール/精製水を加え、80℃にて1時間加温還流で2回抽出し、濾過した抽出液を定法により凍結乾燥した。その結果、乾燥固形分としてそれぞれ16.4g、17.9g、30.3g、27.5g、26.3g、3.5gを得た。
インヨウカクに含まれる公知成分であるicariin及びマリアアザミに含まれる公知成分であるsilybin、silymarinについては、市販の標準品を使用した。
即ち、icariin(LKT, Laboratories, Inc, USA, Lot
No.2591307)、silybin(Extrasynthese, France, Lot No.02112642)及びsilymarin(LKT, Laboratories, Inc, USA, Lot No.2397805)を使用した。
アロマターゼ阻害活性の測定は、既知論文(Sresser DM,Tuner SD,et al.,A High−throughput screen to identify inhibitors of aromatase(CYP19),Analyt
ical Biochemistry,284;427―430,2000.)にて公表された方法に基づき、BD Biosciences社(米国)製の試薬を用いて行った。なお。比較例(ポジティブコントロール)としてはchrysin(Extrasynthese, France, Lot No.06042506)を使用した(図2)。
即ち、96穴マイクロプレートを用い、予め用意したNADPH産生系溶液(NADPH−Cofactor Mix)144μLと被検抽出物溶液6μLとを混合した後、37℃で10分間インキュベートし、酵素と基質の溶液(Enzyme Substrate Mix)100μLを加え混合後、37℃で30分間反応させた。その後、反応停止液75μLを加え、生成した基質の代謝物であるHFC(7−hydroxy−4−trifluoromethyl coumarin)量をプレートリーダー(SPECTRAFluor, TECAN)を用い、励起波長409nm, 蛍光波長 538nmにて蛍光強度を測定することにより求めた。なお、ブランクには、10分間インキュベート後に、酵素と基質の溶液に代わりに反応停止液75μLを添加した。アロマターゼ阻害率は式1により算出した。
A=(被検試料無添加の酵素反応後の吸光度−そのブランクの吸光度)
B=(各濃度の被検試料の酵素反応後の吸光度−その各ブランクの吸光度)
また、非特異的な阻害作用(例えばタンニンによる蛋白凝固作用)を避けるために、試薬に付帯する対照蛋白質をNADPH産生系溶液に添加した。
被検試料溶液については、濃度を段階的に希釈して各濃度における阻害率を求め、その結果から内挿法により、アロマターゼ活性を50%阻害する試料濃度IC50値を求めた。
約400種類の抽出物についてアロマターゼ阻害活性を測定した結果、次の37種類の生薬抽出物に濃度依存的、かつ最高濃度100μg/mLにおいて50%以上の阻害活性が認められた。表1〜4にはこれらの生薬抽出物のIC50値を阻害作用の強い順に示した。
即ち、阻害作用が認められたものは、
紅景天、夏枯草、甘茶、マリアアザミ、ジャスミン茶、ボクソク、甜茶、旱連草、楊梅皮、フランス海岸松、檳榔、アスパラガス、漏芦、良姜、ルイボス茶、大黄、プーアル茶、緑茶、オウゴン、西洋オトギリソウ、甘草、千里光、ウィンターグリーン、訶子、野梧桐、何首烏、インヨウカク、ガラナ、桜皮、艾葉、地黄、山茱萸、細辛、桂皮、芍薬、松葉、アムラの抽出物の計37種類であり、それぞれのIC50値は6.1μg/mL、7.4μg/mL、7.4μg/mL、7.7μg/mL、7.8μg/mL、8.9μg/mL、9.0μg/mL、10.1μg/mL、10.3μg/mL、10.7μg/mL、11.3μg/mL、13.2μg/mL、13.4μg/mL、15.2μg/mL、16.0μg/mL、17.2μg/mL、17.8μg/mL、17.8μg/mL、20.1μg/mL、21.2μg/mL、22.7μg/mL、23.5μg/mL、26.9μg/mL、27.7μg/mL、30.1μg/mL、31.9μg/mL、35.0μg/mL、37.6μg/mL、37.8μg/mL、40.4μg/mL、44.7μg/mL、52.0μg/mL、58.0μg/mL、59.3μg/
mL、72.5μg/mL、78.9μg/mL、98.4μg/mLであった(表1〜4参照)。
これら37種類の生薬は古くから中国及び中国以外の国々でも使われているが、アロマターゼ阻害作用を有することはこれまで全く知られておらず、本発明により初めて得られた新知見である。
これらの化合物はいずれも公知の成分であるが、アロマターゼ阻害活性を有することはこれまで全く知られておらず、本発明により初めて得られた新知見である。
本発明により初めてアロマターゼ阻害活性が見出された37種類の生薬抽出物については、これらを含有する医薬品又は健康食品は、閉経後女性の乳癌のみならず、男性更年期障害及び内臓脂肪蓄積によるメタボリックシンドローム等の性ホルモン依存性疾患の治療及び/又は予防に寄与し得ると考えられる。
また、これらの生薬うちのインヨウカクに含まれる成分であるicariin及びマリアアザミに含まれる成分であるsilybin、silymarinについては、これらを化学修飾することで新規なアロマターゼ阻害剤を開発するための先導化合物を提供することができると期待される。
Claims (2)
- 甜茶の抽出物を含有することを特徴とするアロマターゼ阻害剤。
- 請求項1に記載のアロマターゼ阻害剤を含有することを特徴とするエストロゲン依存性の子宮筋腫、子宮内膜症、子宮内膜癌及び閉経後女性の乳癌、男性ホルモンの減少に起因する男性更年期障害及びテストステロンの減少に起因する内臓脂肪蓄積によるメタボリックシンドロームの治療及び/又は予防剤。
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KR20230015368A (ko) | 2020-06-22 | 2023-01-31 | 가부시키가이샤 니혼야쿠교 | 테스토스테론 분비 촉진제 |
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JP4532599B2 (ja) | 2010-08-25 |
JP2010059191A (ja) | 2010-03-18 |
JPWO2009066712A1 (ja) | 2011-04-07 |
JP2010059190A (ja) | 2010-03-18 |
JP2010059189A (ja) | 2010-03-18 |
JP4554722B2 (ja) | 2010-09-29 |
JP4532600B2 (ja) | 2010-08-25 |
WO2009066712A1 (ja) | 2009-05-28 |
JP2010059187A (ja) | 2010-03-18 |
US20120040026A1 (en) | 2012-02-16 |
US20100255127A1 (en) | 2010-10-07 |
CN102335219A (zh) | 2012-02-01 |
CN102335269A (zh) | 2012-02-01 |
JP2010059192A (ja) | 2010-03-18 |
JP2010059186A (ja) | 2010-03-18 |
CN102335269B (zh) | 2013-06-19 |
JP2010059188A (ja) | 2010-03-18 |
JP4532598B2 (ja) | 2010-08-25 |
CN101868243A (zh) | 2010-10-20 |
JP4521476B2 (ja) | 2010-08-11 |
JP4536822B2 (ja) | 2010-09-01 |
US20120070514A1 (en) | 2012-03-22 |
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