Quinone thioether-mediated DNA damage, growth arrest, and gadd153 expression in renal proximal tubular epithelial cells.
Quinone thioether-mediated DNA damage, growth arrest, and gadd153 expression in renal proximal tubular epithelial cells.
复制标题
DOI：
--
复制
发表时间：
1996-09
影响因子：
3.6
通讯作者：
J. Jeong;J. Stevens;S. Lau;T. Monks
中科院分区：
文献类型：
--
作者：
J. Jeong;J. Stevens;S. Lau;T. Monks
虽然醌与谷胱甘肽的结合与解毒过程有关，但该反应经常促进醌诱导的毒性。醌类的巯基缀合物保留了氧化还原循环和产生活性氧（ROS）的能力，有助于多种多酚化合物的生物（再）活性。2-溴-双（谷胱甘肽-S-基）氢醌（2-Br-bis（GSyl）HQ）和2-溴-6-（谷胱甘肽-S-基）氢醌[2-Br-6-（GSyl）HQ]是大鼠中的强效肾毒性物质，在体内诱导快速核溶解和培养的肾近端小管上皮细胞（LLC-PK 1）中的DNA单链断裂。我们研究了LLC-PK 1细胞暴露于2-Br-双（GSyl）HQ和2-Br-6-（GSyl）HQ后引发的细胞和分子反应。这两种醌硫醚导致DNA单链断裂的浓度依赖性形成，迅速（2-10分钟）抑制DNA合成，并增加gadd 153的表达，gadd 153是一种对生长停滞和DNA损伤敏感的基因。向暴露于2-Br-6-（GSyl）HQ或2-Br-双（GSyl）HQ的LLC-PK 1细胞中添加过氧化氢酶有效地阻止了gadd 153诱导，这与gadd 153基因受到氧化还原调节以及ROS在醌硫醚介导的细胞毒性中起重要作用的发现一致。去铁胺预处理也减少了gadd 153的诱导，这表明在肾近端肾小管上皮细胞中，gadd 153的表达减少并不依赖于过氧化氢本身的去除，而是防止羟基自由基的产生。细胞内钙与乙二醇-双（β-氨基乙醚）-N，N，N '，N'-四乙酸-乙酰氧基-甲基酯的螯合也减少了2-Br-6-（GSyl）HQ和2-Br-bis（GSyl）HQ对gadd 153的诱导，表明钙在信号传导过程中的作用。因此，2-Br-6-（GSyl）HQ和2-Br-双（GSyl）HQ通过信号传导途径激活基因组应激反应，所述信号传导途径可以包括ROS、Ca 2+和DNA损伤。
Although the conjugation of quinones with glutathione is associated with the process of detoxication, the reaction frequently facilitates quinone-induced toxicity. Thiol conjugates of quinones retain the ability to redox cycle and generate reactive oxygen species (ROS), contributing to the biological (re)activity of a variety of polyphenolic compounds. 2-Bromo-bis(glutathion-S-yl) hydroquinone (2-Br-bis(GSyl)HQ) and 2-bromo-6-(glutathion-S-yl) hydroquinone [2-Br-6-(GSyl)HQ] are potent nephrotoxicants in rats, inducing rapid karyolysis in vivo and DNA single-strand breaks in cultured renal proximal tubular epithelial cells (LLC-PK1). We investigated the cellular and molecular responses initiated after exposure of LLC-PK1 cells to 2-Br-bis(GSyl)HQ and 2-Br-6-(GSyl)HQ. Both quinone thioethers cause the concentration-dependent formation of DNA single-strand breaks, rapidly (2-10 min) inhibit DNA synthesis, and increase the expression of gadd153, a gene responsive to growth arrest and DNA damage. The addition of catalase to LLC-PK1 cells exposed to 2-Br-6-(GSyl)HQ or 2-Br-bis(GSyl)HQ effectively prevents gadd153 induction, which is consistent with findings that the gadd153 gene is subject to redox modulation and that ROS play an important role in quinone thioether-mediated cytotoxicity. Deferoxamine pretreatment also diminishes gadd153 induction, suggesting that in renal proximal tubular epithelial cells, decreased expression of gadd153 is not dependent on the removal of hydrogen peroxide per se but rather on preventing the generation of hydroxyl radical. Chelation of intracellular calcium with ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid-acetoxy-methyl ester also reduces gadd153 induction by 2-Br-6-(GSyl)HQ and 2-Br-bis(GSyl)HQ, suggesting a role for calcium in the signaling process. Thus, 2-Br-6-(GSyl)HQ and 2-Br-bis(GSyl)HQ activate a genomic stress response via a signaling pathway that may include ROS, Ca2+, and DNA damage.