Protective effects of hydrogen sulfide anions against acetaminophen-induced hepatotoxicity in mice
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The key mechanism for hepatotoxicity resulting from acetaminophen (APAP) overdose is cytochrome P450-dependent formation of <i>N</i>-acetyl-<i>p</i>-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 <i>N</i>-acetylcysteine as a sole antidote. Recent evidence from <i>in vitro</i> experiments suggested that sulfide anions (S<sup>2–</sup>) to yield hydrogen sulfide anions (HS<sup>–</sup>) under physiological pH could effectively react with NAPQI. This study evaluated the protective roles of HS<sup>–</sup> against APAP-induced hepatotoxicity in mice. We utilized cystathionine γ-lyase-deficient (<i>Cth</i><sup>–/–</sup>) mice that are highly sensitive to acetaminophen toxicity. Intraperitoneal injection of acetaminophen (150 mg/kg) into <i>Cth</i><sup>–/–</sup> 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<sup>–</sup> 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.
- The Journal of Toxicological Sciences
The Journal of Toxicological Sciences 40(6), 837-841, 2015
The Japanese Society of Toxicology