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マウス四塩化炭素およびカルバマゼピン肝障害モデルにおける肝臓内プロスタグランジンE2量の調節因子に関する研究

大場 憲一 近畿大学

2023.01.19

概要

肝臓は栄養素のエネルギー代謝や貯蔵,タンパク質の合成, 胆汁の生成と分泌,生体異物の解毒に働く生命の維持に必要不可欠な臓器である。さらに種々の内因性生理活性物質の代謝や排泄にも重要な役割を果たしており,肝臓の機能が障害されるとビリルビンの胆汁中排泄が減少することで黄疸や,アンモニア代謝不全により肝性脳症が生じる等の様々な症状が現れる。肝臓機能障害の発症原因は,主にウイルス性,アルコール性,非アルコール性脂肪性,自己免疫性,ならびに薬物性の 5 種類に分類される。その中でも薬物誘発性肝障害 (Drug-induced liver injury, DILI) の発症率が最も高い [1, 2]。新薬候補化合物の治験段階における開発中止や,上市後の医薬品の市場撤退の最大の理由は有効性上の問題だが,次いで副作用惹起など安全性上の問題が挙げられる。DILI は薬物の副作用の中でも特に重篤であり,臨床試験中止および市販後の撤退事例の主たる要因である [3]。

DILI はその特徴により,中毒性肝障害と特異体質性肝障害に分類される。中毒性肝障害は,服用した薬物の用量に依存して惹起される。中毒性肝障害の例として, acetoaminophen (APAP) があげられ,欧米では自殺目的の APAP 過剰服用が肝障害原因の第 1 位である [1, 2]。一方,特異体質性肝障害は,服用した薬物の用量に依存せずに薬物代謝酵素,受容体,トランスポーターなどの遺伝子多型による薬物感受性や薬物動態の個人差などの遺伝的要因や食事,飲酒,喫煙および疾患による環境要因などの個人の体質に依存して発症する。したがって, 発症が非常にまれであり予測が困難である。様々な薬物によって特異体質性肝障害が惹起されるが, diclofenac (DIC) などの非ステロイド性抗炎症薬 (NSAIDs) ,amoxicillin などの抗菌薬,carbamazepine (CBZ) などの抗てんかん薬 などは肝障害の発症頻度が高い薬物として挙げられる [4]。中毒性および特異体 質性肝障害ともに, その発症には薬物が肝代謝されることにより生じる化学的 に不安定な反応性代謝物が寄与する場合が多い。薬物の反応性代謝物の例とし ては cytochrome P450 (CYP) により生成するキノンイミンやエポキシド等の構造 を有する代謝物や,カルボキシル基を有する薬物のグルクロン酸抱合により生 成するアシルグルクロン酸抱合体などが挙げられる [5]。これらの反応性代謝物 は酸化ストレス,免疫原性,ミトコンドリア障害等によって肝障害を惹起する ことが知られている。薬物による特異体質性肝障害発症の個体差の原因として は,以前から CYP や UDP-glucuronosyl transferase (UGT) などの薬物代謝酵素や organic anion transporting polypeptide (OATP) や multidrug resistance associated protein (MRP) などの薬物トランスポーターの遺伝子変異に伴う反応性代謝物の 体内動態変動が示唆されてきた [6-8]。また近年では, ヒト白血球抗原や免疫系 の遺伝子変異が DILI リスクと関連することが報告されている [9]。したがって,従来の研究では,DILI 発症のメカニズムとして反応性代謝物の化学的特性に加 えて,反応性代謝物の体内動態調節に関わる因子,反応性代謝物によって引き 起こされる免疫応答に関わる因子の遺伝子変異に着目した研究が推進されてき た。しかし, 特異体質性肝障害発症の個体差の原因は未だ完全に明らかにされ ていない。そこで本論文では炎症反応や,免疫応答,組織修復反応の調節に重要な内因性生理活性物質の 1 つであるprostaglandine E2 (PGE2) に着目した。PGE2は種々の肝障害に対して保護的に作用することが知られているため,肝組織中 PGE2 の量や作用の変動は DILI の発症や肝障害の程度の個体差に影響する可能性がある。しかし, 肝障害時の内因性肝 PGE2 量の調節について特異体質性肝障害のみならず,中毒性肝障害についてもこれまでほとんど検討されてこなかった。そこで本論文では中毒性および特異体質性肝障害時の肝組織中PGE2 量の調節因子について検討した。

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