Comparative expression of two alpha class glutathione S-transferases in human adult and prenatal liver tissues.
Comparative expression of two alpha class glutathione S-transferases in human adult and prenatal liver tissues.
复制标题
两种 α 类谷胱甘肽 S-转移酶在成人和产前肝组织中的比较表达。
DOI：
10.1016/s0006-2952(02)01017-1
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发表时间：
2002
影响因子：
5.8
通讯作者：
Gardner,JamesL
中科院分区：
文献类型：
--
作者：
Gallagher,EvanP;Gardner,JamesL
胎儿对经胎盘药物和化学品的解毒能力可能是致畸和发育毒性的关键决定因素。α类谷胱甘肽S-转移酶（GST）的发育调控表达是特别感兴趣的，因为这些同工酶对与致畸有关的氧化损伤的过氧化副产物具有高活性。本研究旨在检测人胎儿肝脏α类GST同工酶的表达和催化活性。北方分析表明，hGSTA 1和/或A2（hGSTA 1/2）和hGSTA 4稳态mRNA在孕中期产前肝脏的存在。产前肝蛋白的Western印迹法通过检测细胞质和线粒体中的hGSTA 1/2反应蛋白和仅线粒体中的hGSTA 4 -4反应蛋白提供了佐证。催化研究表明，产前肝细胞溶质GST对1-氯-2，4-二硝基苯（通用GST参考底物）、δ5-雄烯-3，17-二酮（对hGSTA 1 -1相对特异）和4-羟基壬烯醛（氧化损伤期间产生的高度致突变性α，β-不饱和醛和hGSTA 4 -4底物）具有活性。总谷胱甘肽过氧化物酶和GST依赖的过氧化物酶活性分别高9倍和18倍，在成人肝脏比产前肝脏。多个组织阵列分析表明相当大的组织特异性和发育变化GST mRNA的表达。总之，我们的研究结果表明，存在两个重要的α类GST在孕中期人类产前组织，并表明，线粒体靶向GST可能是一个重要的途径，在产前肝脏细胞毒性产物的去除。此外，相对低效的产前氢过氧化物还原可能是母体转移的促氧化剂药物和化学品的易感性增加的基础。
The ability of the fetus to detoxify transplacental drugs and chemicals can be a critical determinant of teratogenesis and developmental toxicity. Developmentally regulated expression of alpha class glutathione S-transferases (GSTs) is of particular interest, since these isozymes have high activity toward peroxidative byproducts of oxidative injury that are linked to teratogenesis. The present study was initiated to examine the expression and catalytic activities of alpha class GST isozymes in human prenatal liver. Northern analysis demonstrated the presence of hGSTA1 and/or A2 (hGSTA1/2) and hGSTA4 steady-state mRNAs in second trimester prenatal livers. Western blotting of prenatal liver proteins provided corroborating evidence via detection of an hGSTA1/2-reactive protein in both cytosol and mitochondria and of hGSTA4-4-reactive protein in mitochondria alone. Catalytic studies demonstrated that prenatal liver cytosolic GSTs were active toward 1-chloro-2,4-dinitrobenzene (a general GST reference substrate), δ5-androstene-3,17-dione (relatively specific for hGSTA1-1), and 4-hydroxynonenal, a highly mutagenic α,β-unsaturated aldehyde produced during oxidative damage and a substrate for hGSTA4-4. Total GSH-peroxidase and GST-dependent peroxidase activities were 9- and 18-fold higher, respectively, in adult liver than in prenatal liver. Multiple tissue array analyses demonstrated considerable tissue-specific and developmental variation in GST mRNA expression. In summary, our results demonstrate the presence of two important alpha class GSTs in second trimester human prenatal tissues, and indicate that mitochondrial targeting of GST may represent an important pathway for removal of cytotoxic products in prenatal liver. Furthermore, the relatively inefficient prenatal reduction of hydroperoxides may underlie an increased susceptibility to maternally transferred pro-oxidant drugs and chemicals.