title: Teratogenic effects of thalidomide: molecular mechanisms.
abstract: Fifty years ago, prescription of the sedative thalidomide caused a worldwide epidemic of multiple birth defects. The drug is now used in the treatment of leprosy and multiple myeloma. However, its use is limited due to its potent teratogenic activity. The mechanism by which thalidomide causes limb malformations and other developmental defects is a long-standing question. Multiple hypotheses exist to explain the molecular mechanism of thalidomide action. Among them, theories involving oxidative stress and anti-angiogenesis have been widely supported. Nevertheless, until recently, the direct target of thalidomide remained elusive. We identified a thalidomide-binding protein, cereblon (CRBN), as a primary target for thalidomide teratogenicity. Our data suggest that thalidomide initiates its teratogenic effects by binding to CRBN and inhibiting its ubiquitin ligase activity. In this review, we summarize the biology of thalidomide, focusing on the molecular mechanisms of its teratogenic effects. In addition, we discuss the questions still to be addressed.
authors.affiliation: Solutions Research Laboratory, Tokyo Institute of Technology, 4259 Nagatsuda-cho, Midori-ku, Yokohama 226-8503, Japan. takumii@bio.titech.ac.jp
authors.forename: Takumi
authors.initials: T
authors.lastname: Ito
authors.forename: Hideki
authors.initials: H
authors.lastname: Ando
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Handa
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002642:Chick Embryo; D051524:Fibroblast Growth Factor 8 / Q000096:biosynthesis; D006801:Humans; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects; D010447:Peptide Hydrolases / Q000378:metabolism*; D011817:Rabbits; D013045:Species Specificity; D013723:Teratogens / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D013792:Thalidomide / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors; D015027:Zebrafish
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C502543:CRBN protein, human; D013723:Teratogens; D051524:Fibroblast Growth Factor 8; D013792:Thalidomide; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases