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

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

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)837-841
Number of pages5
JournalJournal of Toxicological Sciences
Volume40
Issue number6
DOIs
Publication statusPublished - 2015 Nov 10
Externally publishedYes

Keywords

  • Acetaminophen
  • Glutathione
  • Hepatotoxicity
  • Hydrogen sulfide
  • N-acetyl-p-benzoquinone imine

ASJC Scopus subject areas

  • Toxicology

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