Free radical-mediated oxidative DNA damage in the mechanism of thalidomide teratogenicity.
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.
Parman
T
T
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
Wiley
M J
MJ
Wells
P G
PG
D000818:Animals; D003497:Cyclic N-Oxides; D004249:DNA Damage; D004351:Drug Resistance; D020964:Embryo Loss; D004622:Embryo, Mammalian / Q000378:metabolism* / Q000473:pathology; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D005609:Free Radicals; D006554:Hernia, Umbilical; D006993:Hypnotics and Sedatives / Q000009:adverse effects / Q000378:metabolism*; D017880:Limb Deformities, Congenital / Q000209:etiology*; D051379:Mice; D009589:Nitrogen Oxides / Q000494:pharmacology; D010084:Oxidation-Reduction; D011247:Pregnancy; D011817:Rabbits; D013045:Species Specificity; D013723:Teratogens / Q000378:metabolism*; D013792:Thalidomide / Q000009:adverse effects / Q000378:metabolism*
D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D005609:Free Radicals; D006993:Hypnotics and Sedatives; D009589:Nitrogen Oxides; D013723:Teratogens; C029217:phenyl-N-tert-butylnitrone; D013792:Thalidomide