Differential inhibition of protein synthesis: a possible biochemical mechanism of thalidomide teratogenesis

A theory concerning the chemical and biochemical mechanisms of thalidomide teratogenesis is presented. A considerable body of evidence suggests that the glutarimide ring of thalidomide may exert its biological activity because of its resemblance to the imide pyrimidines thymine and uracil. In addition to the glutarimide ring, thalidomide contains a moderately reactive phthalimide moiety, which allows the spontaneous formation of various glutarimide derivatives in fetal tissues. A model is proposed in which the phthalimide group reacts with small nucleophiles, most likely the polyamines, to produce a derivative(s) having a similar biochemical potential to that of cycloheximide, a glutarimide which is a powerful inhibitor of the elongation phase of protein synthesis. Interference in the elongation phase results in the selective inhibition of the translation of messages which have a high translational efficiency. Evidence is reviewed concerning the differential inhibition or protein synthesis by cycloheximide and the effects of this inhibition on various biochemical and biological processes which are critical during development and differentiation. A similar biochemical activity by the putative thalidomide derivative(s) could explain its extreme teratogenic potential. A number of parallels between the biological effects of thalidomide and cycloheximide are discussed which support the idea that a similar biochemical activity is involved. The theory readily explains many of the observed biological effects of thalidomide including the large difference between fetal and adult toxicity. In addition, evidence is reviewed which suggests that the teratogenic properties of a number of drugs which are structurally related to thalidomide may have a common chemical basis due to the similarity of their imide core structures to thymine and uracil.