DNA Damage by 3,6-Dihydropyrazine-2,5-Dipropanoic Acid, the Cyclic Dimerization Product of 5-Aminolevulinic Acid
DNA Damage by 3,6-Dihydropyrazine-2,5-Dipropanoic Acid, the Cyclic Dimerization Product of 5-Aminolevulinic Acid
复制标题
3,6-二氢吡嗪-2,5-二丙酸（5-氨基乙酰丙酸的环状二聚产物）对 DNA 的损伤
作者：
P. C. Teixeira;J. Onuki;M. Medeiros;D. Dörnemann;P. Mascio
摘要5-氨基乙酰丙酸(ALA)是一种在铅中毒和先天性卟啉症中蓄积的血红素前体。它被证明在金属催化的有氧氧化过程中产生活性氧物种，并对蛋白质、脂质体、DNA和亚细胞结构造成氧化损伤。研究还表明，丙氨酸可以缩合生成环状产物3，6-二氢吡嗪2，5-二丙酸(DHPY)。在这里，我们认为DHPY可能参与了高浓度ALA存在下的DNA损伤。琼脂糖凝胶电泳法显示，在0.1 mM的Cu2+离子存在下，pUC19 DNA暴露于低浓度的DHPY(2×10M)中会引起DNA链断裂。电化学检测表明，在Cu2+存在下，DHPY能促进单体2-脱氧鸟苷的氧化生成8-氧-7，8-二氢-2-脱氧鸟苷。添加金属螯合剂(0.5 mM)、DNA紧凑型多胺亚精胺(1 MM)和精胺(1 MM)或抗氧化酶，如超氧化物歧化酶(10 g/ml)和过氧化氢酶(20 g/ml)可保护DNA免受这些损伤。本文讨论了急性间歇性门静脉症患者肝癌发生率增加的相关数据。
Abstract 5-Aminolevulinic acid (ALA) is a heme precursor that accumulates in lead poisoning and inborn porphyrias. It has been shown to produce reactive oxygen species upon metalcatalyzed aerobic oxidation and to cause oxidative damage to proteins, liposomes, DNA, and subcellular structures. Studies have also shown that ALA may condense to yield the cyclic product 3,6-dihydropyrazine 2,5-dipropanoic acid (DHPY). Here we propose that DHPY could be involved in DNA damage in the presence of high concentrations of ALA. Exposure of plasmid pUC19 DNA to low concentrations of DHPY (2 10 M) in the presence of 0.1 mM Cu[2+] ions causes DNA strand breaks, as demonstrated by agarose gel electrophoresis. It was also shown that in the presence of Cu[2+] ions DHPY is able to increase the oxidation of monomeric 2deoxyguanosine to form 8- oxo-7,8-dihydro-2deoxyguanosine as inferred from high performance liquid chromatography measurements using electrochemical detection. Addition of a metal chelator (bathocuproine, 0.5 mM), the DNA compacting polyamines spermidine (1 mM) and spermine (1 mM) or antioxidant enzymes such as superoxide dismutase (10 g/ml) and catalase (20 g/ml) protect the DNA against these damages. The data presented here are discussed with respect to the increased frequency of liver cancer in patients with acute intermittent porphyria.