JP5946104B2 - 肝炎キャリアの検出方法及び装置 - Google Patents
肝炎キャリアの検出方法及び装置 Download PDFInfo
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- JP5946104B2 JP5946104B2 JP2014260998A JP2014260998A JP5946104B2 JP 5946104 B2 JP5946104 B2 JP 5946104B2 JP 2014260998 A JP2014260998 A JP 2014260998A JP 2014260998 A JP2014260998 A JP 2014260998A JP 5946104 B2 JP5946104 B2 JP 5946104B2
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Description
したがって、オフタルミン酸は、ほとんど生合成されない。しかし、図1(B)に示す酸化状態のように、親電子物質や活性酸素種が存在すると、解毒のためにグルタチオンが消費される。グルタチオンの減少によってフィードバック阻害が解除されて、γ-グルタミ
ルシステイン合成酵素が活性化し、グルタチオンとオフタルミン酸が生合成される。オフタルミン酸は肝臓内に蓄積し、血中にも排泄される。このように親電子物質などによって酸化状態になると、肝臓や血液のオフタルミン酸が増加するため、オフタルミン酸は酸化ストレスのバイオマーカーとなる。
健常者および各種肝炎患者から採取した血清(100μl)を標準物質入りのメタノール900μlに入れ、酵素を失活させ、代謝の亢進を止めた。400μlの超純水、1000μlのクロロホルムを加えた後、4℃で5分間、4,600gで遠心した。静置後、分離した水−メタノール相750μlを分画分子量5kDaの遠心限外ろ過フィルターを通過し、除タンパクした。ろ液を凍結乾燥後、Milli−Q水50μlを加え、それをCE−TOFMSおよびLC−MS測定に供した。
CE−TOFMSを用いて、健常者および肝炎患者の血清中の低分子代謝産物を一斉に測定した。
a.キャピラリー電気泳動−電気泳動(CE)の分析条件
キャピラリーには、フューズドシリカキャピラリー(内径50μm、外径350μm、全長100cm)を用いた。緩衝液には、1Mギ酸(pH約1.8)を用いた。印加電圧は、+30kV、キャピラリー温度は20℃で測定した。試料は、加圧法を用いて50mbarで3秒間(約3nl)注入した。
正イオンモードを用い、イオン化電圧は4kV、フラグメンター電圧は75V、スキマー電圧は50V、OctRFV電圧は125Vに設定した。乾燥ガスには窒素を使用し、温度300℃、圧力10psigに設定した。シース液は50%メタノール溶液を用い、質量較正用にレゼルピン(m/z 609.2807)を0.5μMとなるよう混入し10μl/minで送液した。レゼルピン(m/z 609.2807)とメタノールのアダクトイオン(m/z 83.0703)の質量数を用いて得られた全てのデータを自動較正した。
高感度に測定するため、血清中のγ−Glu−Xペプチド類はLC−MSMSを用いて測定した。
分離カラムには、野村化学(Nomula Chemical Co.)社製Develosil RPAQUEOUS-AR-3(
内径2mm×長さ100mm,3μm)を用い、カラムオーブンは30℃に設定した。試料は1μl注入した。移動相Aには0.5%ギ酸、Bにはアセトニトリルを用い、B液が0%(0min)−1%(5min)−10%(15min)−99%(17min)−99%(19min)の流速0.2ml/minのグラジエント溶出法を用いてγ−Glu−Xペプチド類を分離した。
アプライドバイオシステム(Applied Biosystem)社製API3000三連四重極型質量分析計を用い、ポジティブイオンモードのMRMモードで測定した。各質量分析計のパラメータを以下に示した。
イオンスプレー電圧:5.5kV
ネブライザガス圧力:12psi
カーテンガス圧力:8psi
衝突ガス:8unit
窒素ガス温度:550℃
図2に健常者と肝臓がん(HCC)患者の血清中のγ−Glu−Xペプチド類をLC−MSを用いて測定した結果を示す。多くのγ−Glu−Xペプチド類が、健常者に比べ肝臓がん患者(HCC)で増加していることが判明した。また他の肝障害でも、γ−Glu−Xペプチド類の濃度は健常者に比べて有意に高かった。
ln(p/1−p)=b0+b1x1+b2x2+b3x3+ … +bkxk ・・・(1)
というpの回帰式を求めるが、表2中のパラメータの値が、(1)式のb0、b1、…bk
に入る具体的な値となる。(Intercept)は、定数項(b0)の値を指す。
rの値21.5をb2、…、γ−Glu−Pheの値41.5をb5とし、ALTの定量値をx1、γ−Glu−Thrの定量値をx2、…、γ−Glu−Pheの定量値をx5に代
入して具体的な値を出す。推定したパラメータの標準誤差及び95%信頼区間も表中に示す。
率pがどれだけ変化するのかを表すオッズ比が1を超えて最も大きいγ−Glu−Pheの値が薬剤性肝炎(DI)の判定に最も寄与している。一方、オッズ比が0に近いγ−Glu−Leuやγ−Glu−Hisはこれらの物質の増加が、薬剤性肝炎以外(非DI)と判定することに寄与している。ALTはオッズ比が1.04と、変数に増加に伴うpの
変化がない1.0に近いため、寄与が小さく、省略できる可能性がある。
ために、省略できる可能性がある。
the receiver-operating curve:AUC)は、0.81から0.99であり、これらの
バイオマーカーによる各肝臓疾患スクリーニング検査は、高精度に各疾患を特定できることが確認された。特に健常者(C:AUC=0.939)、薬剤性肝障害(DI:AUC=0.998)、無症状B型肝炎キャリア(AHB:AUC=0.933)、無症状C型肝炎キャリア(AHC:AUC=0.944)、肝臓がん(HCC:AUC=0.937)は、本法により極めて高精度に特定されることがわかった。
γ−Glu−Xペプチド類が他の疾患でも上昇するか確認した。図5に肝臓がん患者(HCC)と胃がん患者(gastric cancer:GC)の血清中のγ−Glu−Xペプチド類の濃度を示した。胃がん患者では、γ−Glu−Xペプチド類の濃度は、健常者と同等であり、肝臓がん患者のようなγ−Glu−Xペプチド類の増加は見られなかった。(注 ヘ
リコバクターピロリの感染が胃がんの原因であり、ヘリコバクターピロリの感染によって、酸化ストレスは抑制されるという報告がある(参考文献10)。胃がんは酸化ストレスに曝されていないため、γ−Glu−Xペプチド類の濃度は低いのではと推測される。)
マウスを用いて、γ−Glu−Xペプチド類の生合成機序を解明した。図1(B)に示したように、活性酸素や親電子物質による酸化ストレス条件下では、これらの物質の除去のためにグルタチオンが枯渇し、それに伴い、γ−グルタミルシステイン合成酵素(GCS)が活性化され、各種のアミノ酸が基質(出発物質)となって、γ−Glu−Xジペプチド類やγ−Glu−X−Glyトリペプチド類が生合成されることが判明した。以下に実験手順を示す。
一晩絶食させたオスのマウスにペントバルビタルナトリウム(体重1Kg当たり60mg)を腹膜内注射して麻酔後、γ−グルタミルシステイン合成酵素(GCS)阻害剤であるBSO、親電子物質(GCS活性化剤)であるDiethylmaleate(DEM)、さらに健常として生理食塩水を体重1Kg当たりそれぞれ4mmol/kg(BSO888mg、DEM688mg)を腹腔内に注射した。投与1時間後にマウスから肝臓(約300mg)を採取した(各5回)。
マウスから摘出した肝臓(約300mg)は直ちに内部標準物質入りのメタノール1mlに入れ、ホモジナイズして酵素を失活させ、代謝の亢進を止めた。500μlの純水を加えた後、300μlの溶液を取り出し、200μlのクロロホルムを加え良く攪拌後、さらに4℃で15分間、15000rpmで遠心した。静置後、分離した水−メタノール相300μlを分画分子量5kDaの遠心限外ろ過フィルターを通過し、除タンパクした。ろ液を凍結乾燥後、Milli−Q水50μlを加え、それをCE−TOFMS測定に供した。
生理食塩水(健常)、BSO、DEM投与後のマウスの肝臓および血清中のアミノ酸、γ−Glu−X、γ−Glu−X−Glyペプチド類の測定結果の一部を図6に示す。左から、それぞれの試薬を投与したマウスの肝臓から検出されたアミノ酸(X)、γ−Glu−Xペプチド、γ−Glu−X−Glyペプチドの定量結果、右に血清中のアミノ酸(X)、γ−Glu−Xペプチド、γ−Glu−X−Glyペプチドの定量結果を示す。
チオン)の結果である。肝臓中のグルタチオン量は健常に比較し、BSO、DEM投与マウスでは急激に減少した(BSO投与ではγ−グルタミルシステイン合成酵素が阻害されるためグルタチオンは減少し、親電子物質DEM投与マウスでは解毒のため消費されるからグルタチオンは減少する)。血清からグルタチオン関連物質は検出されなかった。
さらにスレオニン(Thr)の13C、15Nの同位体を腹腔内投与し、親電子物質を生じて酸化ストレスを与えるAPAPを加えたところ、マウスの肝臓からThrの13C、15Nのγ−Glu−Thr、γ−Glu−Thr-Glyが検出され、確かに、酸化
ストレス条件下では、Thrからγ−Glu−Thr、γ−Glu−Thr−Glyが生合成されることが確認された。
単純脂肪肝(SS)などの各種の肝障害の診断も可能である。今回は、各種の肝障害のマーカー候補のAST、ALT、γ−Glu−Xペプチド類の組み合わせの例を記したが、それらに特定されるわけではなく、今後さらに多検体の精査を行うことで、バイオマーカー候補の種類組み合わせは変更される場合もある。
Claims (8)
- 肝臓疾患の検出方法であって、
被検者から採取された血液中のγ−Glu−Gly、γ−Glu−Ser、γ−Glu−Val、γ−Glu−Thr、γ−Glu−Leu、γ−Glu−Gln、γ−Glu−Lys、γ−Glu−Glu、γ−Glu−His、γ−Glu−Phe、γ−Glu−Tyr、及びγ−Glu−Taurineからなる群から選ばれる少なくとも一種のペプチドの含有量を測定するステップと、
前記ペプチドの含有量を健常者の基準レベルと比較するステップと、
前記ペプチドの含有量が前記基準レベルよりも高ければ、前記被験者は肝臓疾患に罹患しているとするステップと、
を含むことを特徴とする、前記肝臓疾患の検出方法。 - 前記肝臓疾患が、肝炎であることを特徴とする、請求項1に記載の肝臓疾患の検出方法。
- 前記肝炎が、無症状肝炎であることを特徴とする、請求項2に記載の肝臓疾患の検出方法。
- 前記肝炎が、薬剤性肝炎、B型肝炎又はC型肝炎であることを特徴とする、請求項2又は3に記載の肝臓疾患の検出方法。
- 肝臓疾患の検出装置であって、
被検者から採取された血液中のγ−Glu−Gly、γ−Glu−Ser、γ−Glu−Val、γ−Glu−Thr、γ−Glu−Leu、γ−Glu−Gln、γ−Glu−Lys、γ−Glu−Glu、γ−Glu−His、γ−Glu−Phe、γ−Glu−Tyr、及びγ−Glu−Taurineからなる群から選ばれる少なくとも一種のペプチドの含有量を測定する手段と、
前記ペプチドの含有量を健常者の基準レベルと比較する手段と、
前記ペプチドの含有量が前記基準レベルよりも高ければ、前記被験者は肝臓疾患に罹患しているとする手段と、
を含むことを特徴とする、前記肝臓疾患の検出装置。 - 前記肝臓疾患が、肝炎であることを特徴とする、請求項5に記載の肝臓疾患の検出装置。
- 前記肝炎が、無症状肝炎であることを特徴とする、請求項6に記載の肝臓疾患の検出装置。
- 前記肝炎が、薬剤性肝炎、B型肝炎又はC型肝炎であることを特徴とする、請求項6又は7に記載の肝臓疾患の検出装置。
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WO2011158590A1 (ja) * | 2010-06-18 | 2011-12-22 | 学校法人 慶應義塾 | 肝臓疾患マーカー、その測定方法、装置及び医薬品の検定方法 |
US9386295B2 (en) | 2010-09-01 | 2016-07-05 | Lg Electronics Inc. | Digital receiver and method for processing 3D content in the digital receiver |
JP6260275B2 (ja) | 2011-06-30 | 2018-01-17 | 味の素株式会社 | 脂肪肝の評価方法、脂肪肝評価装置、脂肪肝評価方法、脂肪肝評価プログラム、脂肪肝評価システム、および端末装置 |
WO2013005790A1 (ja) * | 2011-07-07 | 2013-01-10 | 味の素株式会社 | 生体酸化の評価方法、生体酸化評価装置、生体酸化評価方法、生体酸化評価プログラム、生体酸化評価システム、情報通信端末装置、および生体酸化の予防・改善物質の探索方法 |
JP2013040923A (ja) * | 2011-07-15 | 2013-02-28 | Ajinomoto Co Inc | Nashの評価方法、nash評価装置、nash評価方法、nash評価プログラム、nash評価システム、情報通信端末装置、およびnashの予防・改善物質の探索方法 |
US20140315327A1 (en) * | 2011-12-02 | 2014-10-23 | C2N Diagnostics | Methods for Measuring Concentrations of Biomolecules |
CN103901212B (zh) * | 2014-03-28 | 2015-07-22 | 西北大学 | 一种基于唾液糖结合蛋白鉴别肝系列病的糖芯片及其应用 |
CA2982097A1 (en) * | 2015-04-10 | 2016-10-13 | Social Welfare Organization Saiseikai Imperial Gift Foundation, Inc. | Method for discriminating symptom of hepatic disease |
KR102156994B1 (ko) | 2016-05-31 | 2020-09-17 | 에프. 호프만-라 로슈 아게 | Hcv 코어 항원의 신속한 검출을 위한 전처리 방법 |
EP3373012A1 (en) * | 2017-03-07 | 2018-09-12 | Biopredictive | Method of diagnosis of drug induced liver injury |
CN106977583A (zh) * | 2017-03-31 | 2017-07-25 | 华南理工大学 | 一种寡肽及其制备方法与应用 |
CN107090013A (zh) * | 2017-03-31 | 2017-08-25 | 华南理工大学 | 一种寡肽及其制备方法与应用 |
EP3701263A4 (en) * | 2017-10-25 | 2021-08-11 | Pharmk Corporation | BIOMARKERS OF HEPATIC FUNCTION |
CN110501443B (zh) * | 2019-09-17 | 2020-09-29 | 山东农业大学 | 无创识别/预警脂肪肝奶牛的新型生物标记物 |
KR102521988B1 (ko) * | 2021-07-08 | 2023-04-17 | 경북대학교 산학협력단 | 감마-글루타밀티로신을 포함하는 암 치료 또는 예방용 약제학적 조성물 |
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US5786336A (en) * | 1991-04-29 | 1998-07-28 | Terrapin Technologies, Inc. | Target-selective protocols based on mimics |
US5916878A (en) * | 1995-11-28 | 1999-06-29 | Edward T. Wei | γ-glutamyl and β-aspartyl containing immunomodulator compounds and methods therewith |
JP3620037B2 (ja) * | 1998-09-14 | 2005-02-16 | ニプロ株式会社 | γ−グルタミルトランスフェラーゼ活性測定用試薬 |
DE602004004775T2 (de) * | 2004-08-12 | 2007-11-22 | Roche Diagnostics Gmbh | Verfahren zur Diagnose von Leberfibrose. |
WO2006113522A2 (en) * | 2005-04-15 | 2006-10-26 | Kye-Hyung Paik | Methods of detecting hepatitis c virus |
CA2621910A1 (en) * | 2005-09-07 | 2007-03-15 | Human Metabolome Technologies, Inc. | Method for calibrating detected mass in mass spectrometry system |
FR2893136A1 (fr) * | 2005-11-10 | 2007-05-11 | Sanofi Aventis Sa | Procedes de diagnostic de maladies hepatiques et de criblage de molecules pour le traitement de ces maladies |
JP4840804B2 (ja) * | 2006-01-20 | 2011-12-21 | 学校法人慶應義塾 | 酸化ストレスの判定方法 |
US7824871B2 (en) * | 2007-06-14 | 2010-11-02 | George Mason Intellectual Properties | Methods of diagnosing non-alcoholic steatohepatitis (NASH) |
EP2227689B1 (en) * | 2007-11-02 | 2012-12-26 | Metabolon, Inc. | Biomarkers for fatty liver disease and methods using the same |
CA2733518A1 (en) * | 2008-08-06 | 2010-02-11 | Sciclone Pharmaceuticals, Inc. | Treatment or prevention of hepatitis c with immunomodulator compounds |
JP2011232164A (ja) * | 2010-04-27 | 2011-11-17 | Keio Gijuku | 肝臓疾患マーカー、その測定方法、装置及び医薬品の検定方法 |
WO2011158590A1 (ja) * | 2010-06-18 | 2011-12-22 | 学校法人 慶應義塾 | 肝臓疾患マーカー、その測定方法、装置及び医薬品の検定方法 |
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CN104198718A (zh) | 2014-12-10 |
WO2010073870A1 (ja) | 2010-07-01 |
EP2381259B1 (en) | 2016-09-21 |
EP2381259A1 (en) | 2011-10-26 |
CN102265160B (zh) | 2014-07-23 |
JPWO2010073870A1 (ja) | 2012-06-14 |
JP2015057616A (ja) | 2015-03-26 |
US20130330749A1 (en) | 2013-12-12 |
EP2381259A4 (en) | 2012-06-20 |
US20110256561A1 (en) | 2011-10-20 |
JP5676275B2 (ja) | 2015-02-25 |
CN104198718B (zh) | 2017-11-10 |
CN102265160A (zh) | 2011-11-30 |
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