Mitochondrial and nuclear DNA damage induced by 5-aminolevulinic acid
Mitochondrial and nuclear DNA damage induced by 5-aminolevulinic acid
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DOI：
10.1016/j.abb.2004.09.030
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发表时间：
2004-12-15
影响因子：
3.9
通讯作者：
Di Mascio, P
中科院分区：
文献类型：
--
作者：
Onuki, J;Chen, YM;Di Mascio, P
5-氨基乙酰丙酸（ALA）是急性间歇性卟啉病（AIP）患者血浆和器官中积累的血红素前体，AIP是一种与神经肌肉功能障碍和肝细胞癌（HCC）发病率增加相关的疾病。AIP患者的肝活检显示奇怪形状的线粒体和含有保存完好的线粒体的自噬空泡。ALA在金属催化氧化时产生活性氧，并导致大鼠肝线粒体和DNA损伤的体内和体外损伤。使用定量聚合酶链反应分析，我们证明了ALA诱导人SVNF成纤维细胞和大鼠PC12细胞的核和线粒体DNA的剂量依赖性损伤。经ALA处理的CHO细胞也显示出核DNA损伤，并且人HepG2细胞进入ALA及其二聚化产物DHPY诱导的凋亡和坏死。目前的数据提供了有关ALA遗传毒性的额外信息，加强了其可能参与AIP患者HCC发展的假设。(C)2004年爱思唯尔公司All rights reserved.
5-Aminolevulinic acid (ALA) is a heme precursor accumulated in plasma and in organs in acute intermittent porphyria (AIP), a disease associated with neuromuscular dysfunction and increased incidence of hepatocellular carcinoma (HCC). Liver biopsies of AIP patients showed odd-shaped mitochondria and autophagic vacuoles containing well-preserved mitochondria. ALA yields reactive oxygen species upon metal-catalyzed oxidation and causes in vivo and in vitro impairment of rat liver mitochondria and DNA damage. Using a quantitative polymerase chain reaction assay, we demonstrated that ALA induces a dose-dependent damage in nuclear and mitochondrial DNA in human SVNF fibroblasts and rat PC12 cells. CHO cells treated with ALA also show nuclear DNA damage and human HepG2 cells entered in apoptosis and necrosis induced by ALA and its dimerization product, DHPY. The present data provide additional information on the genotoxicity of ALA, reinforcing the hypothesis that it may be involved in the development of HCC in AIP patients. (C) 2004 Elsevier Inc. All rights reserved.