Enhanced acetaminophen hepatotoxicity in transgenic mice overexpressing BCL-2
Enhanced acetaminophen hepatotoxicity in transgenic mice overexpressing BCL-2
复制标题
DOI：
10.1124/mol.60.5.907
复制
发表时间：
2001-11-01
影响因子：
3.6
通讯作者：
Bruschi, SA
中科院分区：
文献类型：
--
作者：
Adams, ML;Pierce, RH;Bruschi, SA
线粒体在许多药物诱导的细胞死亡中起重要作用，包括过量使用常用镇痛药对乙酰氨基酚（APAP）引起的肝毒性。为了研究与APAP诱导的肝毒性相关的线粒体改变，测定了促凋亡BAX的亚细胞分布。基于BCL-2的抗凋亡特性，我们进一步假设，如果BAX组分是明显的，那么BCL-2过表达可能具有肝保护作用。将具有人bcl-2转基因（-/+）或野生型小鼠（WT; -/-）的小鼠以500或600 mg/kg（i. p.）APAP或非肝毒性异构体N-乙酰间氨基苯酚（AMAP）。免疫印迹分析表明，增加线粒体BAX-β含量后，APAP或AMAP治疗非常早。这是由BAX-alpha从APAP处理的动物的胞质溶胶中消失所证实的，并且在较小程度上，用AMAP处理。在bcl-2（-/+）小鼠中观察到APAP诱导的3区坏死的早期病理学证据，24 h时进展为大面积全小叶坏死伴出血。相比之下，给予APAP的WT小鼠表现出更典型的小叶中心坏死，且不太严重。AMAP处理的bcl-2（-/+）小鼠仅表现出早期微泡脂肪变性，而没有进展为广泛坏死。早在给药后6 h，复合物III活性明显降低，与24 h时的血浆酶活性相关性良好（AST r（2）= 0.89，ALT r（2）= 0.87），从而证实了线粒体在APAP介导的肝毒性中的作用。总之，这些数据首次表明BAX可能是APAP介导的肝毒性的早期决定因素，BCL-2过表达意外地增强APAP肝毒性。
Mitochondria play an important role in the cell death induced by many drugs, including hepatotoxicity from overdose of the popular analgesic, acetaminophen (APAP). To investigate mitochondrial alterations associated with APAP-induced hepatotoxicity, the subcellular distribution of proapoptotic BAX was determined. Based on the antiapoptotic characteristics of BCL-2, we further hypothesized that if a BAX component was evident then BCL-2 overexpression may be hepatoprotective. Mice, either with a human bcl-2 transgene (-/+) or wild-type mice (WT; -/-), were dosed with 500 or 600 mg/kg (i.p.) APAP or a nonhepatotoxic isomer, N-acetyl-m-aminophenol (AMAP). Immunoblot analyses indicated increased mitochondrial BAX-beta content very early after APAP or AMAP treatment. This was paralleled by disappearance of BAX-alpha from the cytosol of APAP treated animals and, to a lesser extent, with AMAP treatment. Early pathological evidence of APAP-induced zone 3 necrosis was seen in bcl-2 (-/+) mice, which progressed to massive panlobular necrosis with hemorrhage by 24 h. In contrast, WT mice dosed with APAP showed a more typical, and less severe, centrilobular necrosis. AMAP-treated bcl-2 (-/+) mice displayed only early microvesicular steatosis without progression to extensive necrosis. Decreased complex III activity, evident as early as 6 h after treatment, correlated well with plasma enzyme activities at 24 h (AST r(2) = 0.89, ALT r(2) = 0.87) thereby confirming a role for mitochondria in APAP-mediated hepatotoxicity. In conclusion, these data suggest for the first time that BAX may be an early determinant of APAP-mediated hepatotoxicity and that BCL-2 overexpression unexpectedly enhances APAP hepatotoxicity.