Possible involvement of an acylation mechanism in thalidomide‐induced teratogenesis of the newt (Pleurodeles waltl.)

An acylation reaction of biological polyamines by thalidomide has been postulated to explain the teratogenic activity of this drug (Fabro et al. 1965). In a further study, thalidomide has been reported to acylate polyamines at physiological pH; the teratogenic activity of this drug appears to be linked to its high acylating power towards polyamines (Audit 1994). In the present study, the action of the thalidomide molecule and its two chemical moieties (phthalimide and glutarimide rings) on Pleurodeles embryonic development has been investigated. The phthalimide moiety, which displays acylating activity, appears to generate Pleurodeles teratogenesis. The occurrence of a correlation between acylating activity and teratogenicity was confirmed using homothalidomide and partially hydrolyzed thalidomide. The glutarimide moiety has been found to act as an enhancer of phthalimide activity and to cause moderate alterations of newt development. As the acylation of polyamines by thalidomide would deprive the embryo of these essential compounds, the effects of polyamine biosynthesis inhibitors have been compared to those of thalidomide. Both thalidomide and polyamine antimetabolites altered the early cleavage process of the Pleurodeles egg and arrested early development.