The Dihydroxy Metabolite of the Teratogen Thalidomide Causes Oxidative DNA Damage.
The Dihydroxy Metabolite of the Teratogen Thalidomide Causes Oxidative DNA Damage.
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甲状酸酯的二羟基代谢产物会导致氧化性DNA损伤。
DOI：
10.1021/acs.chemrestox.7b00127
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发表时间：
2017-08-21
影响因子：
4.1
通讯作者：
Chowdhury G
中科院分区：
文献类型：
--
作者：
Wani TH;Chakrabarty A;Shibata N;Yamazaki H;Guengerich FP;Chowdhury G
沙利度胺[α-(N-邻苯二甲酰亚胺)戊二酰亚胺](1)是一种镇静止吐药物，最初于20世纪50年代引入临床用于治疗晨吐。尽管在市场上被认为是完全安全的，但仍有1万多名婴儿出生时就有严重的出生缺陷。沙利度胺被禁用，随后被批准用于治疗多发性骨髓瘤和与麻风相关的并发症。虽然人们对其致畸机制已有50多年的了解，但其致畸机制尚不清楚。文献中提出了多种学说，包括DNA损伤和ROS、抑制血管生成和抑制脑白蛋白。所有的理论都有它们的优点和局限性。尽管最近提出的小脑理论得到了广泛的接受，但它未能解释一些小组报告的新陈代谢和低剂量需求。最近，我们提供了令人信服的结构证据，支持芳烃氧化物和苯二酚活性中间体的存在。然而，这些活性中间体的毒性/致畸能力需要调查。在此，我们报道了沙利度胺的氧化代谢产物二羟基沙利度胺是导致ROS和DNA损伤的原因。我们用细胞系展示了彗星(DNA损伤)和ROS的形成。通过DNA裂解实验，我们还证明了过氧化氢酶、自由基清除剂和去甲肾上腺素能够抑制DNA损伤。提出了一种致畸机制，不仅解释了沙利度胺的DNA损伤特性，而且解释了沙利度胺的新陈代谢、低浓度和物种特异性要求。
Thalidomide [α-(N-phthalimido)glutarimide] (1) is a sedative and antiemetic drug originally introduced into the clinic in the 1950s for the treatment of morning sickness. Although marketed as entirely safe, more than 10,000 babies were born with severe birth defects. Thalidomide was banned and subsequently approved for the treatment of multiple myeloma and complications associated with leprosy. Although known for more than 5 decades, the mechanism of teratogenicity remains to be conclusively understood. Various theories have been proposed in the literature including DNA damage and ROS, inhibition of angiogenesis and inhibition of cereblon. All the theories have their merits and limitation. Although the recently proposed cereblon theory has gained wide acceptance, it fails to explain the metabolism and low dose requirement reported by a number of groups. Recently we have provided convincing structural evidence in support of the presences of arene oxide and the quinone reactive intermediates. However, the ability of these reactive intermediates to impart toxicity/teratogenicity needs investigation. Herein we report that the oxidative metabolite of thalidomide, di-hydroxythalidomide is responsible for generating ROS and DNA damage. We show using cell lines the formation of comet (DNA damage) and ROS. Using DNA cleavage assays we also show that catalase, radical scavengers and desferal is capable of inhibiting DNA damage. A mechanism of teratogenicity is proposed that not only explains the DNA damaging property but the metabolism, low concentration and species specificity requirements of thalidomide.
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影响因子：
3.9
作者：
Klaus, Viola;Hartmann, Tobias;Klotz, Lars-Oliver
通讯作者：
Klotz, Lars-Oliver
影响因子：
4.8
作者：
Debnath, J;Muthuswamy, SK;Brugge, JS
通讯作者：
Brugge, JS
组蛋白去甲基化酶 KDM5B 是基因组稳定性的关键调节因子
DOI：
10.1073/pnas.1324036111
发表时间：
2014-05-13
影响因子：
11.1
作者：
Li, Xin;Liu, Ling;Shi, Lei
通讯作者：
Shi, Lei
影响因子：
4.1
作者：
Chowdhury, Goutam;Murayama, Norie;Yamazaki, Hiroshi
通讯作者：
Yamazaki, Hiroshi
影响因子：
5.8
作者：
Bauer, KS;Dixon, SC;Figg, WD
通讯作者：
Figg, WD