The sedative drug thalidomide ([+]-alpha-phthalimidoglutarimide), once
abandoned for causing birth defects in humans1, has found new
therapeutic license in leprosy and other diseases, with renewed teratological
consequences2. Although the mechanism of teratogenesis3 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 macromolecules4,
5. Similarly,
thalidomide is bioactivated by horseradish peroxidase, and oxidizes DNA6 and glutathione7, indicating free radical-mediated
oxidative stress. Furthermore, thalidomide teratogenicity in rabbits is reduced
by the PHS inhibitor acetylsalicylic acid, indicating PHS-catalyzed bioactivation8. 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 agentalpha-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.
