Glutamate cysteine ligase modifier subunit deficiency and gender as determinants of acetaminophen-induced hepatotoxicity in mice
Glutamate cysteine ligase modifier subunit deficiency and gender as determinants of acetaminophen-induced hepatotoxicity in mice
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DOI：
10.1093/toxsci/kfm165
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发表时间：
2007-10-01
影响因子：
3.8
通讯作者：
Kavanagh, Terrance J.
中科院分区：
文献类型：
--
作者：
McConnachie, Lisa A.;Mohar, Isaac;Kavanagh, Terrance J.
镇痛和解热药物对乙酰氨基酚（APAP）被生物活化为反应性中间体N-乙酰基-对-苯醌亚胺，其被谷胱甘肽（GSH）清除。APAP过量可耗尽GSH，导致APAP-蛋白加合物蓄积和肝脏小叶中心坏死。N-乙酰半胱氨酸（NAC）是一种半胱氨酸前体和GSH前体，通常用于治疗APAP过量。谷氨酸半胱氨酸连接酶（GCL）是谷胱甘肽生物合成的限速步骤，它是由催化和修饰亚基（GCLM）组成的异源二聚体。先前的研究表明，GCL活性可能是APAP毒性的重要决定因素。在这项研究中，我们研究了APAP毒性，NAC或GSH乙酯（GSHee）介导的救援与正常或受损的GCLM表达的小鼠。Gclm野生型、杂合型和无效型小鼠单独施用APAP（500 mg/kg），或在NAC（800 mg/kg）或GSHee（168 mg/kg）后立即施用，并在6小时后评估肝毒性。APAP导致所有小鼠GSH耗竭。通过血清丙氨酸氨基转移酶活性和组织病理学评估，Gclm基因缺失和杂合子小鼠比野生型小鼠表现出更广泛的肝损伤。此外，雄性Gclm野生型小鼠表现出比雌性野生型小鼠更大的APAP诱导的肝毒性。与NAC或GSHee的共治疗减轻了APAP在Gclm野生型和杂合子小鼠中的作用，但在Gclm缺失小鼠中没有。总的来说，这些数据重申了GSH在保护APAP诱导的肝毒性中的重要性，并表明GCL活性和性别在APAP诱导的小鼠肝损伤中的关键作用。
The analgesic and antipyretic drug acetaminophen (APAP) is bio-activated to the reactive intermediate N-acetyl-p-benzoquinoneimine, which is scavenged by glutathione (GSH). APAP overdose can deplete GSH leading to the accumulation of APAP-protein adducts and centrilobular necrosis in the liver. N-acetylcysteine (NAC), a cysteine prodrug and GSH precursor, is often given as a treatment for APAP overdose. The rate-limiting step in GSH biosynthesis is catalyzed by glutamate cysteine ligase (GCL) a heterodimer composed of catalytic and modifier (GCLM) subunits. Previous studies have indicated that GCL activity is likely to be an important determinant of APAP toxicity. In this study, we investigated APAP toxicity, and NAC or GSH ethyl ester (GSHee)-mediated rescue in mice with normal or compromised GCLM expression. Gclm wild-type, heterozygous, and null mice were administered APAP (500 mg/kg) alone, or immediately following NAC (800 mg/kg) or GSHee (168 mg/kg), and assessed for hepatotoxicity 6 h later. APAP caused GSH depletion in all mice. Gclm null and heterozygous mice exhibited more extensive hepatic damage compared to wild-type mice as assessed by serum alanine aminotransferase activity and histopathology. Additionally, male Gclm wild-type mice demonstrated greater APAP-induced hepatotoxicity than female wild-type mice. Cotreatment with either NAC or GSHee mitigated the effects of APAP in Gclm wild-type and heterozygous mice, but not in Gclm null mice. Collectively, these data reassert the importance of GSH in protection against APAP-induced hepatotoxicity, and indicate critical roles for GCL activity and gender in APAP-induced liver damage in mice.