RNA as a new target for toxic and protective agents
RNA as a new target for toxic and protective agents
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DOI：
10.1016/j.mrfmmm.2008.09.003
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发表时间：
2008-12-15
影响因子：
2.3
通讯作者：
Hrelia, Patrizia
中科院分区：
文献类型：
--
作者：
Fimognari, Carmela;Sestili, Piero;Hrelia, Patrizia
与基因组DNA损伤相反，尽管RNA损伤有可能影响细胞生理学，但RNA损伤在生物医学研究中是一个缺乏研究的领域。RNA损伤的潜在触发因素及其病理生理学意义在很大程度上仍然未知。虽然比基因组中的突变更不致命，但这种对细胞的非急性致命损伤最近与几种人类慢性疾病的潜在机制有关。我们通过测试一系列具有不同作用机制的化学物质的RNA损伤活性来研究RNA损伤是否与特定外源性物质的暴露有关。培养的人T淋巴母细胞用甲磺酸乙酯（EMS）、H2 O2、阿霉素、精胺或5-亚硝基-N-乙酰青霉胺（SNAP）。此外，我们研究了石榴提取物对不同化学物质引起的RNA损伤的潜在保护活性。特别注意的是提取物的保护机制。石榴的保护作用可以通过改变毒性剂吸收和摄取的速率、通过捕获亲电体以及自由基以及保护RNA中的亲核位点来介导。我们使用了两种不同的治疗方案（预处理和共处理），以了解石榴的抑制活性的机制。我们证明了总RNA易受化学攻击。阿霉素、H_2O_2、精胺和SNAP均可降解总RNA。然而，EMS，一种众所周知的DNA损伤剂，缺乏RNA损伤特性，而精胺和SNAP，虽然缺乏DNA损伤特性，但能够损伤RNA。P2 O3降低了阿霉素、H2 O2和精胺的RNA损伤作用。其抑制活性可能与其与阿霉素和H2 O2形成复合物的能力有关，或与介导其毒性的反应性物质的细胞内形成相互作用。对于精胺，也可以涉及精胺吸收和摄取速率的改变。(C)2008 Elsevier B. V.保留所有权利。
In contrast to damage of genomic DNA and despite its potential to affect cell physiology, RNA damage is a poorly examined field in biomedical research. Potential triggers of RNA damage as well as its pathophysiological implications remain largely unknown. While less lethal than mutations in genome, such non-acutely lethal insults to cells have been recently associated with underlying mechanisms of several human chronic diseases. We investigated whether RNA damage could be related to the exposure of particular xenobiotics by testing the RNA-damaging activity of a series of chemicals with different mechanisms of action. Cultured human T-lymphoblastoid cells were treated with ethyl methanesulfonate (EMS), H2O2., doxorubicin, spermine, or 5-nitroso-N-acetylpenicillamine (SNAP). Furthermore, we studied the potential protective activity of a pomegranate extract against RNA damage induced by different chemicals. Special attention has been paid to the protective mechanisms of the extract. The protective effect of pomegranate can be mediated by alterations of the rates of toxic agent absorption and uptake, by trapping of electrophiles as well as free radicals, and protection of nucleophilic sites in RNA. We used two different treatment protocols (pre- and co-treatment) for understanding the mechanism of the inhibitory activity of pomegranate. We demonstrated that total RNA is susceptible to chemical attack. A degradation of total RNA could be accomplished with doxorubicin, H2O2, spermine and SNAP. However, EMS, a well-known DNA-damaging agent, was devoid of RNA-damaging properties, while spermine and SNAP, although lacking of DNA-damaging properties, were able to damage RNA. Pomegranate reduced the RNA-damaging effect of doxorubicin, H2O2, and spermine. Its inhibitory activity could be related with its ability to forms complexes with doxorubicin and H2O2, or interacts with the intracellular formation of reactive species mediating their toxicity. For spermine, an alteration of the rates of spermine absorption and uptake can also be involved. (C) 2008 Elsevier B.V. All rights reserved.