Protective effects of hydrogen sulfide anions against acetaminophen-induced hepatotoxicity in mice

DOI Web Site Web Site PubMed 被引用文献2件 参考文献14件 オープンアクセス
  • Ishii Isao
    Department of Biochemistry, Keio University Graduate School of Pharmaceutical Sciences
  • Kamata Shotaro
    Department of Biochemistry, Keio University Graduate School of Pharmaceutical Sciences
  • Hagiya Yoshifumi
    Department of Biochemistry, Keio University Graduate School of Pharmaceutical Sciences
  • Abiko Yumi
    Graduate School of Comprehensive Human Sciences, University of Tsukuba
  • Kasahara Tadashi
    Department of Biochemistry, Keio University Graduate School of Pharmaceutical Sciences
  • Kumagai Yoshito
    Graduate School of Comprehensive Human Sciences, University of Tsukuba

この論文をさがす

抄録

The key mechanism for hepatotoxicity resulting from acetaminophen (APAP) overdose is cytochrome P450-dependent formation of N-acetyl-p-benzoquinone imine (NAPQI), a potent electrophilic metabolite that forms protein adducts. The fundamental roles of glutathione in the effective conjugation/clearance of NAPQI have been established, giving a molecular basis for the clinical use of N-acetylcysteine as a sole antidote. Recent evidence from in vitro experiments suggested that sulfide anions (S2–) to yield hydrogen sulfide anions (HS–) under physiological pH could effectively react with NAPQI. This study evaluated the protective roles of HS– against APAP-induced hepatotoxicity in mice. We utilized cystathionine γ-lyase-deficient (Cth–/–) mice that are highly sensitive to acetaminophen toxicity. Intraperitoneal injection of acetaminophen (150 mg/kg) into Cth–/– mice resulted in highly elevated levels of serum alanine/aspartate aminotransferases and lactate dehydrogenase associated with marked increases in oncotic hepatocytes; all of which were significantly inhibited by intraperitoneal preadministration of sodium hydrosulfide (NaHS). NaHS preadministration significantly suppressed APAP-induced serum malondialdehyde level increases without abrogating APAP-induced rapid depletion of hepatic glutathione. These results suggest that exogenous HS– protects hepatocytes by directly scavenging reactive NAPQI rather than by increasing cystine uptake and thereby elevating intracellular glutathione levels, which provides a novel therapeutic approach against acute APAP poisoning.

収録刊行物

被引用文献 (2)*注記

もっと見る

参考文献 (14)*注記

もっと見る

関連プロジェクト

もっと見る

キーワード

詳細情報 詳細情報について

問題の指摘

ページトップへ