Free radical-mediated oxidative DNA damage in the mechanism of thalidomide teratogenicity
Free radical-mediated oxidative DNA damage in the mechanism of thalidomide teratogenicity
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DOI：
10.1038/8466
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发表时间：
1999-05-01
期刊：
影响因子：
82.9
通讯作者：
Wells, PG
中科院分区：
文献类型：
--
作者：
Parman, T;Wiley, MJ;Wells, PG
镇静药物沙利度胺（[+]-α-邻苯二甲酰亚胺戊二酰亚胺），曾经因导致人类出生缺陷而被放弃，现在已经在麻风病和其他疾病中发现了新的治疗许可证，并重新产生了致畸后果（2）。尽管致畸作用的机制（3）和风险的决定因素仍不清楚，但相关的致畸异生物质被胚胎前列腺素H合酶（PHS）生物活化为产生活性氧（ROS）的自由基中间体，这会导致DNA和其他细胞大分子的氧化损伤（4，5）。类似地，沙利度胺被辣根过氧化物酶生物活化，并氧化DNA（6）和谷胱甘肽（7），表明自由基介导的氧化应激。此外，PHS抑制剂乙酰水杨酸可降低沙利度胺在家兔中的致畸性，表明PHS催化的生物活化作用（8）。在这里，我们表明，在兔子，沙利度胺启动胚胎DNA氧化和致畸性，这两个被取消的自由基自旋捕获剂α-苯基-N-叔丁基硝酮（PBN）的预处理。相比之下，在小鼠中，一种对沙利度胺致畸性有抗性的物种，沙利度胺不会增强DNA氧化，即使剂量比兔子高300%，这为物种依赖性易感性的胚胎决定因素提供了见解。除了它们的治疗意义，这些结果构成了直接证据表明，沙利度胺的致畸性可能涉及自由基介导的氧化损伤胚胎细胞大分子。
The sedative drug thalidomide ([+]-alpha-phthalimidoglutarimide), once abandoned for causing birth defects in humans', has found new therapeutic license in leprosy and other diseases, with renewed teratological consequences(2). Although the mechanism of teratogenesis(3) and determinants of risk remain unclear, related teratogenic xenobiotics are bioactivated by embryonic prostaglandin H synthase (PHS) to a free-radical intermediates that produce reactive oxygen species (ROS), which cause oxidative damage to DNA and other cellular macromolecules(4,5) Similarly, thalidomide is bioactivated by horseradish peroxidase, and oxidizes DNA(6) and glutathione(7), indicating free radical-mediated oxidative stress. Furthermore, thalidomide teratogenicity in rabbits is reduced by the PHS inhibitor acetylsalicylic acid, indicating PHS-catalyzed bioactivation(8). Here, we show in rabbits that thalidomide initiates embryonic DNA oxidation and teratogenicity, both of which are abolished by pre-treatment with the free radical spin trapping agent alpha-phenyl-N-t-butylnitrone (PBN). In contrast, in mice, a species resistant to thalidomide teratogenicity, thalidomide does not enhance DNA oxidation, even at a dose 300% higher than that used in rabbits, providing insight into an embryonic determinant of species-dependent susceptibility. In addition to their therapeutic implications, these results constitute direct evidence that the teratogenicity of thalidomide may involve free radical-mediated oxidative damage to embryonic cellular macromolecules.