Sex difference in susceptibility to acetaminophen hepatotoxicity is reversed by buthionine sulfoximine
Sex difference in susceptibility to acetaminophen hepatotoxicity is reversed by buthionine sulfoximine
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DOI：
10.1016/j.tox.2011.05.018
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发表时间：
2011-09-05
期刊：
影响因子：
4.5
通讯作者：
Watanabe, Yasuko
中科院分区：
文献类型：
--
作者：
Masubuchi, Yasuhiro;Nakayama, Junpei;Watanabe, Yasuko
性别是影响个体对实验动物和人类药物性肝损伤易感性的一个因素。在这项研究中，我们研究了对乙酰氨基酚（APAP）诱导的雌性小鼠肝毒性的抵抗机制。对禁食过夜的雄性和雌性CD-1小鼠腹膜内给予APAP。在雌性小鼠中，以导致雄性小鼠严重肝毒性的剂量给予APAP后，观察到血清丙氨酸氨基转移酶水平轻微升高。在肝毒性发生前，两种性别小鼠的肝脏谷胱甘肽（GSH）迅速耗尽，而雌性小鼠的恢复速度比雄性小鼠快。这与雌性动物中肝谷氨酸-半胱氨酸连接酶（GCL）的诱导较高一致。用GCL抑制剂L-丁硫基乙砜亚胺（BSO）预处理小鼠，仅在雌性小鼠中加重APAP肝毒性，导致雌性小鼠的肝毒性远高于雄性小鼠。此外，与雄性小鼠相比，BSO预处理雌性小鼠的肝脏GSH显著耗竭，这支持BSO预处理雌性小鼠的重度肝毒性。APAP治疗仅在雌性小鼠中高度诱导多药耐药相关蛋白4（Mrp 4）。由此产生的高Mrp 4表达，从而可能有助于降低肝GSH水平通过正弦流出时，GCL被抑制。总之，抗APAP肝毒性雌性小鼠和其逆转预处理BSO可归因于性别差异的处置肝GSH，这通常可以确定药物诱导的肝损伤的敏感性。(C)2011爱思唯尔爱尔兰有限公司保留所有权利。
Gender is a factor that influences susceptibility of individuals to drug-induced liver injury in experimental animals and humans. In this study, we investigated the mechanisms underlying resistance of female mice to acetaminophen (APAP)-induced hepatotoxicity. Overnight-fasted male and female CD-1 mice were administered APAP intraperitoneally. A minor increase in serum alanine aminotransferase levels was observed in female mice after APAP administration at a dose that causes severe hepatotoxicity in males. Hepatic glutathione (GSH) depleted rapidly in the both genders prior to development of hepatotoxicity, whereas its recovery was more rapid in female than in male mice. This was consistent with higher induction of hepatic glutamate-cysteine ligase (GCL) in females. Pretreatment of mice with L-buthionine sulfoximine (BSO), an inhibitor of GCL, exaggerated APAP hepatotoxicity only in female mice, resulting in much higher hepatotoxicity in female than in male mice. In addition, hepatic GSH was markedly depleted in BSO-pretreated female mice compared with male mice, which supports severe hepatotoxicity in BSO-pretreated females. APAP treatment highly induced multidrug resistance-associated protein 4 (Mrp4) only in female mice. The resulting high Mrp4 expression could thus contribute to decreased hepatic GSH levels via sinusoidal efflux when GCL is inhibited. In conclusion, resistance to APAP hepatotoxicity in female mice and its reversal by pretreatment with BSO could be attributed to sex differences in disposition of hepatic GSH, which may generally determine susceptibility to drug-induced liver injury. (C) 2011 Elsevier Ireland Ltd. All rights reserved.