Exacerbation of gefitinib-induced liver injury by glutathione reduction in mice.
Exacerbation of gefitinib-induced liver injury by glutathione reduction in mice.
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DOI：
10.2131/jts.45.493
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Shingo Oda;Nanaka Miyazaki;K. Tsuneyama;T. Yokoi
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作者：
Shingo Oda;Nanaka Miyazaki;K. Tsuneyama;T. Yokoi
吉非替尼（GEF）是第一个选择性表皮生长因子受体酪氨酸激酶抑制剂。它与临床药物性肝损伤的发生有关。虽然GEF通过细胞色素P450 3A和1A酶代谢为化学反应性代谢物，然后与谷胱甘肽（GSH）结合，但这些反应性代谢物是否有助于GEF诱导的毒性仍然未知。在这项研究中，我们调查是否GSH耗竭可以敏感小鼠GEF引起的肝损伤。雄性C57 BL/6 J小鼠用700 mg/kg的L-丁硫氨酸（S，R）-亚砜亚胺（BSO）腹腔内预处理以抑制GSH合成，然后每24小时口服给予500 mg/kg的GEF，连续4天。BSO和GEF的联合给药使血浆丙氨酸氨基转移酶（ALT）水平分别在首次给药后72和96小时升高至约700 U/L和1600 U/L，而单独接受500 mg/kg GEF的小鼠血浆ALT水平的升高有限，表明GSH在GEF诱导的肝损伤中起保护作用。组织学检查显示BSO+GEF联合给药小鼠肝脏中出现核破裂和散发性单个肝细胞死亡。在这些小鼠中，血红素加氧酶1（Hmox 1）和金属硫蛋白2（Mt 2）mRNA的肝脏表达水平，半胱天冬酶3/7酶活性，和2-硫代巴比妥酸反应物质的量显着增加，表明存在氧化应激，这可能与肝细胞死亡。总之，这些结果表明，氧化应激以及GEF的反应性代谢产物参与GEF诱导的GSH耗竭小鼠肝损伤。
Gefitinib (GEF) is the first selective tyrosine kinase inhibitor of epidermal growth factor receptor. It is associated with the occurrence of clinical drug-induced liver injury. Although GEF is metabolized to chemically reactive metabolites by cytochrome P450 3A and 1A enzymes and then conjugated to glutathione (GSH), whether these reactive metabolites contribute to GEF-induced toxicity remains unknown. In this study, we investigated whether GSH depletion can sensitize mice to liver injury caused by GEF. Male C57BL/6J mice were intraperitoneally pretreated with L-buthionine (S,R)-sulfoximine (BSO) at 700 mg/kg to inhibit GSH synthesis and then orally administered GEF at 500 mg/kg every 24 hr for 4 consecutive days. The coadministration of BSO and GEF increased plasma alanine aminotransferase (ALT) levels to approximately 700 U/L and 1600 U/L at 72 and 96 hr after the first administration, respectively, whereas the increase in plasma ALT levels in mice receiving GEF at 500 mg/kg alone was limited, suggesting that GSH plays a protective role in GEF-induced liver injury. Histological examination showed nuclear karyorrhexis and sporadic single hepatocyte death in the livers of BSO+GEF coadministered mice. In these mice, the hepatic expression levels of heme oxygenase 1 (Hmox1) and metallothionein 2 (Mt2) mRNA, caspase 3/7 enzymatic activity, and the amounts of 2-thiobarbiuric acid reactive substances were significantly increased, suggesting the presence of oxidative stress, which may be associated with hepatocellular death. Together, these results show that oxidative stress as well as the reactive metabolites of GEF are involved in GEF-induced liver injury in GSH-depleted mice.