POSSIBLE INVOLVEMENT OF AN ACYLATION MECHANISM IN THALIDOMIDE-INDUCEDTERATOGENESIS 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 acyla te polyamines at physiological pH; the teratogenic activity of this dr ug appears to be linked to its high acylating power towards polyamines (Audit 1994). In the present study, the action of the thalidomide mol ecule and its two chemical moieties (phthalimide and glutarimide rings ) on Pleurodeles embryonic development has been investigated. The phth alimide moiety, which displays acylating activity, appears to generate Pleurodeles teratogenesis. The occurrence of a correlation between ac ylating activity and teratogenicity was confirmed using homothalidomid e and partially hydrolyzed thalidomide. The glutarimide moiety has bee n found to act as an enhancer of phthalimide activity and to cause mod erate 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 ea ly cleavage process of the Pleurodeles egg and arrested early development.