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

Isao Ishii, Shotaro Kamata, Yoshifumi Hagiya, Yumi Abiko, Tadashi Kasahara, Yoshito Kumagai

研究成果: Letter査読

6 被引用数 (Scopus)

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.

本文言語English
ページ(範囲)837-841
ページ数5
ジャーナルJournal of Toxicological Sciences
40
6
DOI
出版ステータスPublished - 2015 11 10

ASJC Scopus subject areas

  • 毒物学

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