Shull G E
J Theor Biol. 1984 Oct 5;110(3):461-86. doi: 10.1016/s0022-5193(84)80187-3.
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.
本文提出了一种关于沙利度胺致畸作用的化学和生化机制的理论。大量证据表明，沙利度胺的戊二酰亚胺环可能因其与嘧啶类碱基胸腺嘧啶和尿嘧啶的相似性而发挥其生物活性。除了戊二酰亚胺环外，沙利度胺还含有一个具有中等反应活性的邻苯二甲酰亚胺部分，这使得它能在胎儿组织中自发形成各种戊二酰亚胺衍生物。本文提出了一个模型，其中邻苯二甲酰亚胺基团与小分子亲核试剂（很可能是多胺）反应，生成一种具有与环己酰亚胺类似生化潜能的衍生物，环己酰亚胺是一种戊二酰亚胺，是蛋白质合成延伸阶段的强力抑制剂。对延伸阶段的干扰导致对具有高翻译效率的信使RNA翻译的选择性抑制。本文回顾了有关环己酰亚胺对蛋白质合成的差异抑制以及这种抑制对发育和分化过程中各种关键生化和生物过程的影响的证据。推测的沙利度胺衍生物具有类似的生化活性，可以解释其极高的致畸潜能。本文讨论了沙利度胺和环己酰亚胺生物效应之间的一些相似之处，这些相似之处支持了它们涉及类似生化活性的观点。该理论很容易解释沙利度胺许多已观察到的生物效应，包括胎儿毒性和成人毒性之间的巨大差异。此外，本文还回顾了证据，这些证据表明，一些与沙利度胺结构相关的药物的致畸特性可能由于其酰亚胺核心结构与胸腺嘧啶和尿嘧啶的相似性而具有共同的化学基础。
