Oxidative DNA Damage by Vitamin A and Its Derivative via Superoxide Generation*
Oxidative DNA Damage by Vitamin A and Its Derivative via Superoxide Generation*
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DOI：
10.1074/jbc.275.3.2003
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发表时间：
2000-01
期刊：
影响因子：
--
通讯作者：
M. Murata;S. Kawanishi
中科院分区：
文献类型：
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作者：
M. Murata;S. Kawanishi
最近的干预研究表明，吸烟者补充β-胡萝卜素导致肺癌发病率升高。然而，因果机制仍有待澄清。本文报道了维生素A（视黄醇）及其衍生物（视黄醛）引起细胞DNA断裂的脉冲场凝胶电泳检测。Retinol和retinal可显著诱导HL-60细胞中8-oxo-7，8-dihydro-2′-deoxyguanosine的生成，但对H2 O2抗性的HP-100细胞无此作用，提示H2 O2参与了细胞DNA损伤。使用32 P标记的分离的DNA的实验表明，视黄醇和视黄醇引起的Cu（II）介导的DNA损伤，这是抑制过氧化氢酶。紫外-可见光谱和电子自旋共振捕获的研究表明，产生的超氧和碳中心的自由基，分别。类维生素A自氧化过程中超氧阴离子的产生与8-氧-7，8-二氢-2 ′-脱氧鸟苷的形成密切相关，但碳中心自由基的产生与DNA损伤的强度没有必然的关系。这些结果表明，超氧化物产生的类维生素A的自氧化歧化为H2 O2，这是负责DNA损伤的内源性金属的存在下。视黄醇和视黄醛具有促氧化作用，β-胡萝卜素的补充可能导致致癌。
Recent intervention studies revealed that β-carotene supplement to smokers resulted in a higher incidence of lung cancer. However, the causal mechanisms remain to be clarified. We reported here that vitamin A (retinol) and its derivative (retinal) caused cellular DNA cleavage detected by pulsed field gel electrophoresis. Retinol and retinal significantly induced 8-oxo-7,8-dihydro-2′-deoxyguanosine formation in HL-60 cells but not in H2O2-resistant HP100 cells, suggesting the involvement of H2O2 in cellular DNA damage. Experiments using 32P-labeled isolated DNA demonstrated that retinol and retinal caused Cu(II)-mediated DNA damage, which was inhibited by catalase. UV-visible spectroscopic and electron spin resonance-trapping studies revealed the generation of superoxide and carbon-centered radicals, respectively. The superoxide generation during autoxidation of retinoids was significantly correlated with the formation of 8-oxo-7,8-dihydro-2′-deoxyguanosine, although the yield of carbon-centered radicals was not necessarily related to the intensity of DNA damage. These findings suggest that superoxide generated by autoxidation of retinoids was dismutated to H2O2, which was responsible for DNA damage in the presence of endogenous metals. Retinol and retinal have prooxidant abilities, which might lead to carcinogenesis of the supplements of β-carotene.