Molecular Toxicology Group, Department of Biology, University of Konstanz, Universitaetsstrasse 10, 78457 Konstanz, Germany.
Toxicol In Vitro. 2018 Aug;50:29-39. doi: 10.1016/j.tiv.2018.02.001. Epub 2018 Feb 10.
Psychological stress has been associated with DNA damage, thus increasing the risk of numerous diseases including cancer. Here, we investigate the effect of acute and chronic stress on poly(ADP-ribose) polymerase-1 (PARP-1), a sensor of DNA damage and DNA repair initiator. In order to mimic the chronic release of epinephrine, human peripheral blood mononuclear cells (PBMCs) were treated repeatedly with the sympathomimetic drug isoproterenol. We found significant induction of DNA strand breaks that remained unrepaired 24 h after ex vivo incubation. Isoproterenol-induced DNA strand breaks could be partially prevented by pre-treatment with the β-adrenergic receptor antagonist propranolol. Furthermore, the level of PARP-1 protein and PARP activity decreased and the levels of the PARP substrate nicotinamide adenine dinucleotide (NAD) and of adenosine triphosphate (ATP), necessary to replenish NAD pools, were lowered by isoproterenol treatment. In conclusion our data provide novel insights into the mechanisms of isoproterenol-induced genotoxicity linking β-adrenergic stimulation and PARP-1.
心理压力与 DNA 损伤有关，从而增加了多种疾病的风险，包括癌症。在这里，我们研究了急性和慢性应激对多聚（ADP-核糖）聚合酶-1（PARP-1）的影响，PARP-1 是 DNA 损伤的传感器和 DNA 修复启动子。为了模拟肾上腺素的慢性释放，我们反复用拟交感神经药物异丙肾上腺素处理人外周血单核细胞（PBMC）。我们发现，在体外孵育 24 小时后，仍存在明显的 DNA 链断裂诱导而未修复。β-肾上腺素能受体拮抗剂普萘洛尔预处理可部分预防异丙肾上腺素诱导的 DNA 链断裂。此外，PARP-1 蛋白水平和 PARP 活性降低，异丙肾上腺素处理还降低了 PARP 底物烟酰胺腺嘌呤二核苷酸（NAD）和三磷酸腺苷（ATP）的水平，NAD 池的补充需要这些物质。总之，我们的数据提供了异丙肾上腺素诱导的遗传毒性的新见解，将β-肾上腺素能刺激与 PARP-1 联系起来。
