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

Abstract

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.

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Figure 1: Effect of PBN on thalidomide-initiated DNA oxidation in pregnant rabbits.
Figure 2: Effect of PBN on thalidomide-initiated DNA oxidation in pregnant mice.
Figure 3: Effect of PBN on thalidomide teratogenicity.

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Acknowledgements

These studies were supported by a grant to PGW from the Medical Research Council of Canada. Preliminary reports of this research were presented at the 36th and 38th annual meetings of the Society of Toxicology (USA): Fundam. Appl. Toxicol. 36(S1,P2): 303 (Number 1542), 1997; Toxicol. Sci. 48(1-S): 17 (Number 79), 1999).

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Correspondence to Peter G. Wells.

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Parman, T., Wiley, M. & Wells, P. Free radical-mediated oxidative DNA damage in the mechanism of thalidomide teratogenicity. Nat Med 5, 582–585 (1999). https://doi.org/10.1038/8466

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