METAL-MEDIATED OXIDATIVE DAMAGE TO CELLULAR AND ISOLATED DNA BY CERTAIN TRYPTOPHAN-METABOLITES
METAL-MEDIATED OXIDATIVE DAMAGE TO CELLULAR AND ISOLATED DNA BY CERTAIN TRYPTOPHAN-METABOLITES
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DOI：
10.1093/carcin/16.2.349
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发表时间：
1995-02-01
期刊：
影响因子：
4.7
通讯作者：
KAWANISHI, S
中科院分区：
文献类型：
--
作者：
HIRAKU, Y;INOUE, S;KAWANISHI, S
色氨酸代谢物3-羟基邻氨基苯甲酸（3-HAA）和3-羟基犬尿氨酸（3-HKyn）是致癌物质。研究了金属离子存在下3-HAA和3-HKyn对DNA的损伤，作为其致癌性的潜在机制。脉冲凝胶电泳显示，在Mn（II）的存在下，3-HAA和3-HKyn诱导培养的人细胞的DNA双链断裂。DNA单链断裂与碱处理观察。过氧化氢酶抑制剂对链断裂的促进作用和邻菲咯啉对链断裂的抑制作用表明H_2O_2和内源性过渡金属离子的参与。用DNA测序技术研究了c-Ha-ras-1原癌基因DNA片段的损伤。3-HAA和3-HKyn诱导哌啶不稳定的网站经常在胸腺嘧啶和鸟嘌呤残基的Cu（II）的存在下。浴铜灵和过氧化氢酶对Cu（II）介导的DNA损伤的抑制作用表明，Cu（I）和H2 O2在导致DNA损伤的活性物种的产生中具有重要作用。3-HAA与Mn（II）预孵育可增强Cu（II）介导的DNA损伤。紫外-可见光谱表明，Mn（II）和Cu（II）以不同的方式提高了3-HAA的自氧化速率。这些结果表明，在Mn（II）或Cu（II）的存在下，这些色氨酸代谢产物产生H2 O2，其被过渡金属离子激活，从而在分离的DNA和培养的细胞的情况下对DNA造成损伤。
The tryptophan metabolites 3-hydroxyanthranilic acid (3-HAA) and 3-hydroxykynurenine (3-HKyn) are carcinogens. DNA damage by 3-HAA and 3-HKyn in the presence of metal ions was investigated as a potential mechanism of their carcinogenicity. Pulsed held gel electrophoresis showed that in the presence of Mn(II), 3-HAA and 3-HKyn induced DNA double-strand breaks in cultured human cells. DNA single-strand breaks were observed with alkali treatment. The enhancing effect of catalase inhibitor and the inhibitory effect of o-phenanthroline on the strand breakage indicated the involvement of H2O2 and endogenous transition metal ion. Damage to DNA fragments obtained from c-Ha-ras-1 protooncogene was investigated by a DNA sequencing technique. 3-HAA and 3-HKyn induced piperidine-labile sites frequently at thymine and guanine residues in the presence of Cu(II). The inhibitory effects of bathocuproine and catalase on Cu(II)-mediated DNA damage suggest that Cu(I) and H2O2 have important roles in the production of active species causing DNA damage. The Cu(II)-mediated DNA damage was enhanced by preincubation of 3-HAA with Mn(II). UV-visible spectroscopy showed that Mn(II) and Cu(II) enhanced the rate of autoxidation of 3-HAA in different ways. These results suggest that in the presence of Mn(II) or Cu(II), these tryptophan metabolites produce H2O2, which is activated by transition metal ion to cause damage to DNA both in the case of isolated DNA and cultured cells.