02542nas a2200397   4500000000100000008004100001260001300042653001200055653002000067653001500087653002000102653001600122653002200138653001100160653002800171653001800199653002200217653002800239653003300267653000900300653002000309653002400329653001400353653001200367653002400379653001500403653001600418100001300434700001400447700001400461245009500475300001000570490000600580520154400586022001402130       1999                            d  c1999 May10aAnimals10aCyclic N-Oxides10aDNA Damage10aDrug Resistance10aEmbryo Loss10aEmbryo, Mammalian10aFemale10aFree Radical Scavengers10aFree Radicals10aHernia, Umbilical10aHypnotics and Sedatives10aLimb Deformities, Congenital10aMice10aNitrogen Oxides10aOxidation-Reduction10aPregnancy10aRabbits10aSpecies Specificity10aTeratogens10aThalidomide1 aParman T1 aWiley M J1 aWells P G00aFree radical-mediated oxidative DNA damage in the mechanism of thalidomide teratogenicity.  a582-50 v53 a<p>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.</p>  a1078-8956