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Free radical-mediated oxidative DNA damage in the mechanism of thalidomide teratogenicity.

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  • المؤلفون: Parman T;Parman T; Wiley MJ; Wells PG
  • المصدر:
    Nature medicine [Nat Med] 1999 May; Vol. 5 (5), pp. 582-5.
  • نوع النشر :
    Comparative Study; Journal Article; Research Support, Non-U.S. Gov't
  • اللغة:
    English
  • معلومة اضافية
    • المصدر:
      Publisher: Nature Publishing Company Country of Publication: United States NLM ID: 9502015 Publication Model: Print Cited Medium: Print ISSN: 1078-8956 (Print) Linking ISSN: 10788956 NLM ISO Abbreviation: Nat Med Subsets: MEDLINE
    • بيانات النشر:
      Publication: New York Ny : Nature Publishing Company
      Original Publication: New York, NY : Nature Pub. Co., [1995-
    • الموضوع:
      DNA Damage*; Embryo, Mammalian/*metabolism ; Hypnotics and Sedatives/*metabolism ; Limb Deformities, Congenital/*etiology ; Teratogens/*metabolism ; Thalidomide/*metabolism; Animals ; Cyclic N-Oxides ; Drug Resistance ; Embryo Loss ; Embryo, Mammalian/pathology ; Female ; Free Radical Scavengers/pharmacology ; Free Radicals ; Hernia, Umbilical ; Hypnotics and Sedatives/adverse effects ; Mice ; Nitrogen Oxides/pharmacology ; Oxidation-Reduction ; Pregnancy ; Rabbits ; Species Specificity ; Thalidomide/adverse effects
    • نبذة مختصرة :
      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. Although the mechanism of teratogenesis 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. Similarly, thalidomide is bioactivated by horseradish peroxidase, and oxidizes DNA and glutathione, indicating free radical-mediated oxidative stress. Furthermore, thalidomide teratogenicity in rabbits is reduced by the PHS inhibitor acetylsalicylic acid, indicating PHS-catalyzed bioactivation. 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.
    • Comments:
      Comment in: Nat Med. 1999 May;5(5):489-90. (PMID: 10229222)
      Comment in: Nat Med. 1999 Jul;5(7):715. (PMID: 10395302)
      Comment in: Nat Med. 1999 Aug;5(8):853. (PMID: 10426292)
    • الرقم المعرف:
      0 (Cyclic N-Oxides)
      0 (Free Radical Scavengers)
      0 (Free Radicals)
      0 (Hypnotics and Sedatives)
      0 (Nitrogen Oxides)
      0 (Teratogens)
      3I91332OPG (phenyl-N-tert-butylnitrone)
      4Z8R6ORS6L (Thalidomide)
    • الموضوع:
      Date Created: 19990506 Date Completed: 19990519 Latest Revision: 20131121
    • الموضوع:
      20231215
    • الرقم المعرف:
      10.1038/8466
    • الرقم المعرف:
      10229238