JP2018131389A - アセトアルデヒドデヒドロゲナーゼ活性促進剤 - Google Patents
アセトアルデヒドデヒドロゲナーゼ活性促進剤 Download PDFInfo
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- JP2018131389A JP2018131389A JP2017024038A JP2017024038A JP2018131389A JP 2018131389 A JP2018131389 A JP 2018131389A JP 2017024038 A JP2017024038 A JP 2017024038A JP 2017024038 A JP2017024038 A JP 2017024038A JP 2018131389 A JP2018131389 A JP 2018131389A
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- acetaldehyde
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Abstract
Description
[式(1)中、R1はC1−6アルキル基を示し、R2はC1−6アルキル基又はC2−6アルケニル基を示し、R3はC1−6アルキル基又はC2−6アルケニル基を示し、R4はカルボニル基又は水酸基を示す。]
で表される化合物又はその塩を有効成分として含む、アセトアルデヒドデヒドロゲナーゼ活性促進剤を提供する。
本実施形態に係るアセトアルデヒドデヒドロゲナーゼ活性促進剤は、下記一般式(1):
[式(1)中、R1はC1−6アルキル基を示し、R2はC1−6アルキル基又はC2−6アルケニル基を示し、R3はC1−6アルキル基又はC2−6アルケニル基を示し、R4はカルボニル基又は水酸基を示す。]
で表される化合物(以下、「化合物(1)」ともいう)又はその塩を有効成分として含む。
[式(2)中、R1、R2、R3及びR4は、上記式(1)におけるR1、R2、R3及びR4と同義である。]
で表される化合物が好ましい。
化合物(1)又はその塩を対象(例えば、哺乳動物)に投与することによって、当該対象の血中におけるアセトアルデヒド濃度を低減する効果が奏される。よって、本発明の一実施形態として、上記一般式(1)で表される化合物又はその塩を有効成分として含む、血中アセトアルデヒド低減剤が提供される。なお、上記実施形態において、製剤形態、投与量及び投与方法、用途等については、〔1.アセトアルデヒドデヒドロゲナーゼ活性促進剤〕におけるものと同様である。
ホップエキス(三栄源エフ・エフ・アイ株式会社製)に1N塩酸を加えて懸濁させた後、ヘキサンを添加して水層と有機層に分配した。有機層をエバポレーターで留去することで、イソα酸の濃度が70%のイソα酸含有ホップエキスを得た。
また、文献(Taniguchi Y. et al., Identificationand quantification of the oxidation products derived from α-acids and β-acids during storage of hops(Human lupulus L.), J. Agric. Food Chem., 61(12), 3121-3130(2013))に記載の方法に準じて、シス−イソコフムロン、シス−イソフムロン、及びシス−イソアドムロンの標品を得た。
マウス肝癌由来細胞(Hepa−1c1c7(ECACC:95090613))を12ウェルプレートに2.5×105細胞/ウェルとなるように播種し、37℃、5%CO2の条件下で24時間培養した。培地は、α−MEM(ナカライテスク株式会社製)に、非動化した10% ウシ胎児血清(FBS)、500unit/mLのペニシリン、及び500μg/mLのストレプトマイシンを添加したものを使用した。培養後、上記1.で調製した各試料を添加し、さらに48時間培養した。ここで、イソα酸含有ホップエキスについては終濃度5ppm、10ppm及び25ppmとなるように添加し、シス−イソコフムロン、シス−イソフムロン及びシス−イソアドフムロンについては、各標品の50%アセトニトリル水溶液を終濃度5mM及び15mMとなるように添加した。一方、コントロールについては、50%アセトニトリル水溶液を添加した。培養液を除去し、付着細胞をリン酸緩衝生理食塩水(PBS)で2回洗浄した後、50mM Tris−HCl(pH 8.4)を加えて、スクラーパーにて細胞をこすり落とし、マイクロホモジナイザーでホモジナイズした。このホモジネートを遠心分離し(3,000×g、4℃、15分間)、得られた上清をALDHの活性測定に用いた。
ALDHの活性測定は、以下のように6−メトキシ−2−ナフトアルデヒド(MONAL−62)を基質として、アルデヒド基の酸化により生成する6−メトキシ−2−ナフトエ酸を、蛍光検出器を備えたHPLCで定量することで行った。反応液の全量が200μLとなるように、50mM Tris−HCl(pH 8.4)、1mM ピラゾール、1mM NAD+、上記で得られた上清、及び0.1mM MONAL−62を混合し、37℃で30分間反応させた。得られた反応液にアセトニトリル(800μL)を加え、撹拌してALDHを失活させた後、濾過してHPLCによる6−メトキシ−2−ナフトエ酸定量のための検体を得た。なお、HPLCの分析条件は以下のとおりである。
カラム:Symmetry C18(Waters社製、2.1×50mm、3.5μm)
移動相:A 2.0%ギ酸(0.02%EDTA含有)、B アセトニトリル(2.0%ギ酸含有)、B:36−54%(0.0−4.5min)
流速:0.5ml/min
温度:37℃
検出:FLD(Ex 310nm、Em 360nm)
結果を図1及び2に示す。
上記2.と同様の方法で、試料としてイソα酸含有ホップエキスを添加して培養したマウス肝癌由来細胞(Hepa−1c1c7)からTRIzol(Invitrogen社製、商品名)を用いてtotal RNAを抽出し、RNeasy Mini Kit(QIAGEN社製、商品名)を用いて精製した。cRNAは、total RNAを鋳型としてReverTra Ace(東洋紡株式会社製、商品名)を用いて調製した。
mRNA発現解析は、リアルタイムPCRにて行った。リアルタイムPCRは、LightCycler 480 SYBR Green I Master(Roche社製)を用い、LightCycler 480システム(Roche社製)にて行った。なお、使用したプライマーの配列は以下のとおりである。
ALDH1
TGAACAAGCTGGCTGACTTAATGG(配列番号1)
CGACAAGTATGCATTGGCAAAGAC(配列番号2)
ALDH2
TCTTCATTAACAATGAGTGGCACGA(配列番号3)
AGCAGCCTTCACTGCCTTGTCTA(配列番号4)
β−アクチン
CATCCGTAAAGACCTCTATGCCAAC(配列番号5)
ATGGAGCCACCGATCCACA(配列番号6)
結果を図3に示す。
5週齢の雄性C57BL/6NCrSlcマウスを日本エスエルシー社より購入した。飼育温度24±1℃、湿度48±4%、12時間の明暗サイクル(明期:8時〜20時)の環境下において、AIN−93G(粉末飼料)で1週間の予備飼育を行い、体重を基に2群に分けた。
通常食群(コントロール)は、AIN−93G全量の1.0%をデキストリンで置換した粉末飼料を与えて飼育した。試験食群は、AIN−93G全量の1.0%を上記1.で得られたイソα酸含有ホップエキスで置換した粉末飼料を与えて飼育した。また、総摂餌量の差が通常食群と試験食群との間で生じないようにするため、ペアフィーディングにより給餌量を調節した。
通常食又は試験食を与えて1週間飼育したマウスにアセトアルデヒド(200mg/kg)を腹腔内投与し、眼底静脈より経時採血を行った(アセトアルデヒド投与前、5分後、10分後、及び15分後)。なお、アルコールデヒドロゲナーゼ(ADH)によるアセトアルデヒドの分解を抑えるため、アセトアルデヒドの投与1時間前に4−メチルピラゾール(82mg/kg)を腹腔内投与した。採取した血液(40μL)に0.6N過塩素酸(500μL)を加え、ボルテックスミキサーで撹拌した後、遠心分離(1,500×g、4℃、5分間)し、上清を得た。得られた上清(450μL)を1.5mL容GCバイアルに移し、内部標準液として0.02%t−ブタノール(500μL)を加えて検体とし、ガスクロマトグラフィー(GC)を用いて血中アセトアルデヒド濃度を測定した。なお、GCの分析条件は以下のとおりである。
カラム:Supelcowax(Supelco社製、60m×0.53mm、2.0μm)
キャリアガス:N2、50kPa(定圧)
オーブン:90℃
注入口:110℃
検出:FID、200℃
結果を図4に示す。
上記4.で使用したマウスから肝臓を摘出した。この肝臓に50mM Tris−HCl(pH 8.4、3mL/肝臓1g)を加えて、マイクロホモジナイザーでホモジナイズした。このホモジネートを遠心分離し(9,000×g、4℃、5分間)、得られた上清をALDHの活性測定に用いた。ALDHの活性測定は、上記2.と同様の方法で行った。結果を図5に示す。
上記3.と同様の方法で、上記4.で摘出した肝臓からtotal RNAを抽出した後、リアルタイムPCRにてmRNA発現解析を行った。結果を図6に示す。
Claims (12)
- 前記化合物がイソα酸である、請求項1に記載の剤。
- 前記化合物がシス−イソフムロン又はシス−イソアドフムロンである、請求項1又は2に記載の剤。
- 前記化合物がイソα酸である、請求項4に記載の剤。
- 前記化合物がシス−イソフムロン又はシス−イソアドフムロンである、請求項4又は5に記載の剤。
- 前記化合物がイソα酸である、請求項7に記載の食品組成物。
- 前記化合物がシス−イソフムロン又はシス−イソアドフムロンである、請求項7又は8に記載の食品組成物。
- 前記化合物がイソα酸である、請求項10に記載の食品組成物。
- 前記化合物がシス−イソフムロン又はシス−イソアドフムロンである、請求項10又は11に記載の食品組成物。
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