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安眠药吸收cereblon蛋白导致胎儿畸形

最新一期《Science》杂志报道,半个世纪前,萨利德迈(thalidomide)是孕妇广泛使用的安眠药,但一些孕妇服用安眠药萨利德迈(thalidomide)会产下畸形儿,原因一直不明,日前研究发现,是因为thalidomide药会妨碍对胎儿手足发育非常重要的蛋白质的活动。

该研究是由日本东北大学和日本东京工业大学的研究人员完成的。研究论文指出,他们在直径为万分之二毫米的微小粒子表面附着萨利德迈成分,然后将其放入含有人体癌细胞的液体中,结果发现该药很容易与被称为“cereblon”的蛋白质结合。

在用斑马鱼进行的实验中,研究人员通过基因操纵,抑制了“cereblon”的活动,结果发现斑马鱼胸鳍等发育异常。然后研究人员又通过基因操纵使“cereblon”无法与萨利德迈结合,向受精卵投放萨利德迈成分后,胸鳍等发育并未出现异常。用鸡进行的实验也取得同样结果。

研究小组认为,“cereblon”对于胎儿的四肢发育有着重要作用,与萨利德迈结合以后,其机能受到阻碍,导致畸形。

Science 12 March 2010:Vol. 327. no. 5971, pp. 1345 – 1350 DOI: 10.1126/science.1177319

Identification of a Primary Target of Thalidomide Teratogenicity

Half a century ago, thalidomide was widely prescribed to pregnant women as a sedative but was found to be teratogenic, causing multiple birth defects. Today, thalidomide is still used in the treatment of leprosy and multiple myeloma, although how it causes limb malformation and other developmental defects is unknown. Here, we identified cereblon (CRBN) as a thalidomide-binding protein. CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cul4A that is important for limb outgrowth and expression of the fibroblast growth factor Fgf8 in zebrafish and chicks. Thalidomide initiates its teratogenic effects by binding to CRBN and inhibiting the associated ubiquitin ligase activity. This study reveals a basis for thalidomide teratogenicity and may contribute to the development of new thalidomide derivatives without teratogenic activity.

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