title: Protective effects of hydrogen sulfide anions against acetaminophen-induced hepatotoxicity in mice.
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 (S(2-)) 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.
authors.affiliation: Department of Biochemistry, Keio University Graduate School of Pharmaceutical Sciences.
authors.forename: Isao
authors.initials: I
authors.lastname: Ishii
authors.forename: Shotaro
authors.initials: S
authors.lastname: Kamata
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Hagiya
authors.forename: Yumi
authors.initials: Y
authors.lastname: Abiko
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kasahara
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Kumagai
mesh_terms: D000082:Acetaminophen / Q000378:metabolism / Q000506:poisoning* / Q000633:toxicity*; D000208:Acute Disease; D000818:Animals; D016227:Benzoquinones / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007097:Imines / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013440:Sulfides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D016227:Benzoquinones; D007097:Imines; D013440:Sulfides; D000082:Acetaminophen; D008315:Malondialdehyde; D003577:Cytochrome P-450 Enzyme System; C025451:sodium bisulfide; C028473:N-acetyl-4-benzoquinoneimine; D005978:Glutathione