Thiol involvement in the inhibition of DNA repair by metals in mammalian cells.

Molecular toxicology Pub Date : 1989-04-01
R D Snyder, P J Lachmann
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Abstract

We have previously demonstrated that a number of metal salts have the capacity to inhibit the DNA repair process in human cells. In order to determine a role for non-protein thiols (TNPT) in this inhibition, we investigated repair of X-ray damage in metal-treated HeLa cells under normal conditions and conditions in which cellular thiols had been depleted by treatment with buthionine sulfoximine (BSO) and diethyl maleate (DEM). The combination reduced cellular TNPT by 92%, and cells so depleted became sensitized to X-ray-induced killing and exhibited retarded sealing of X-ray-induced DNA single-strand breaks. Thiol depletion also sensitized cells to the cytotoxicity of certain but not all metals tested. The sensitivity to copper was increased over 6000-fold, and significant enhancement of killing was also seen in cells treated with arsenic, lead, and mercury. Smaller effects were observed with cadmium and nickel, and sensitivity to manganese, magnesium, cobalt or zinc was not substantially altered. Enhanced sensitivity to X-ray killing was found in cells treated with nickel, cadmium, zinc, arsenic, and copper under conditions in which thiols were not limiting. In thiol-depleted cells, sensitivity was not further increased in the case of nickel and arsenic but at least additively affected for copper, mercury and zinc. X-Ray-induced single-strand break repair was retarded by treatment of cells with mercury, nickel, zinc, arsenic, and copper in thiol-normal cells. In thiol-depleted cells, repair inhibition by zinc, arsenic, and copper was nearly complete, while little additional effect on repair was seen following mercury and nickel treatment. An examination of the effects of brief metal treatment on cellular TNPT revealed that copper strongly decreased thiol levels whereas the other metals tested either had no effect on TNPT or reduced TNPT levels to no less than 48% under the conditions employed. No simple relationship appears to exist relating loss of cellular thiols and sensitivity of repair in the series of metals tested. Clear, although indirect, evidence exists, however, that sensitivity to X-rays is mediated through thiols and that the interaction of metals and thiols in the cell may be an important factor in modulating the response to irradiation.

硫醇参与哺乳动物细胞中金属对DNA修复的抑制。
我们之前已经证明了一些金属盐具有抑制人类细胞DNA修复过程的能力。为了确定非蛋白硫醇(TNPT)在这种抑制中的作用,我们研究了金属处理的HeLa细胞在正常条件下和细胞硫醇通过丁硫氨酸亚砜(BSO)和马来酸二乙酯(DEM)处理耗尽的条件下的x射线损伤修复。该组合使细胞TNPT降低了92%,并且细胞对x射线诱导的杀伤变得敏感,并且表现出x射线诱导的DNA单链断裂的延迟密封。硫醇消耗也使细胞对某些但不是所有被测金属的细胞毒性敏感。对铜的敏感性增加了6000多倍,在用砷、铅和汞处理的细胞中,杀伤能力也显著增强。对镉和镍的影响较小,对锰、镁、钴或锌的敏感性没有实质性改变。在硫醇不受限制的条件下,用镍、镉、锌、砷和铜处理的细胞对x射线杀伤的敏感性增强。在硫醇耗尽的电池中,对镍和砷的敏感性没有进一步提高,但对铜、汞和锌的敏感性至少受到附加影响。用汞、镍、锌、砷和铜处理巯基正常细胞,可以延缓x射线诱导的单链断裂修复。在硫醇耗尽的细胞中,锌、砷和铜对修复的抑制几乎完全,而汞和镍处理对修复几乎没有额外的影响。一项对短暂金属处理对细胞TNPT影响的研究表明,铜能显著降低硫醇水平,而在所采用的条件下,其他金属要么对TNPT没有影响,要么将TNPT水平降低到不低于48%。在测试的一系列金属中,似乎不存在有关细胞硫醇损失和修复敏感性的简单关系。然而,存在明确的,尽管是间接的证据,表明对x射线的敏感性是通过硫醇介导的,并且细胞中金属和硫醇的相互作用可能是调节对辐照反应的重要因素。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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