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首页> 外文期刊>The Journal of toxicological sciences >Protective effects of hydrogen sulfide anions against acetaminophen-induced hepatotoxicity in mice
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Protective effects of hydrogen sulfide anions against acetaminophen-induced hepatotoxicity in mice

机译：硫化氢阴离子对乙酰氨基酚引起的小鼠肝毒性的保护作用

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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 gamma-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.
机译：对乙酰氨基酚（APAP）过量引起的肝毒性的关键机制是细胞色素P450依赖的N-乙酰基-对-苯醌亚胺（NAPQI）的形成，NAPQI是一种强大的亲电子代谢产物，可形成蛋白质加合物。已经建立了谷胱甘肽在NAPQI的有效结合/清除中的基本作用，为临床使用N-乙酰半胱氨酸作为唯一解毒剂提供了分子基础。来自体外实验的最新证据表明，在生理pH下产生硫化氢阴离子（HS-）的硫化物阴离子（S2-）可以与NAPQI有效反应。这项研究评估了HS-对小鼠APAP诱导的肝毒性的保护作用。我们利用对对乙酰氨基酚毒性高度敏感的胱硫醚γ裂解酶（Cth（-/-））小鼠。向Cth（-/-）小鼠腹膜内注射对乙酰氨基酚（150 mg / kg），导致血清丙氨酸/天冬氨酸转氨酶和乳酸脱氢酶水平升高，与肿瘤肝细胞明显增加有关;腹膜内预先施用氢硫化钠（NaHS）均显着抑制了所有这些药物。 NaHS预先给药可显着抑制APAP诱导的血清丙二醛水平升高，而不会废除APAP诱导的肝谷胱甘肽快速消耗。这些结果表明，外源性HS-通过直接清除反应性NAPQI而不是通过增加胱氨酸摄取从而提高细胞内谷胱甘肽水平来保护肝细胞，这为急性APAP中毒提供了一种新颖的治疗方法。

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