Piddington R L, Goldman A S
Prog Clin Biol Res. 1985;171:295-306.
The production of cleft palate by glucocorticoids and phenytoin is a complicated interference of a complex developmental program involving many genetic and biochemical processes. The H-2 histocompatibility region includes genes which affect susceptibility to glucocorticoid- and phenytoin-induced cleft palate; glucocorticoid receptor level in a variety of tissues including maternal and embryonic palates, adult thymuses and lungs; and the degree of inhibition of prostaglandin and thromboxane production by glucocorticoids and phenytoin in thymocytes. A gene linked to a minor histocompatibility locus (H-3) on the second chromosome also influences susceptibility to glucocorticoid and phenytoin-induced cleft palate. Phenytoin is an alternate ligand for the glucocorticoid receptor affecting prostaglandin and/or thromboxane production. The capacity of glucocorticoids to induce cleft palate is correlated with their anti-inflammatory potency. At least some of the anti-inflammatory effects of glucocorticoids can be explained by the inhibition of prostaglandin and/or thromboxane release, which in turn could be caused by inhibition of arachidonic acid release from phospholipids. Similar mechanisms may be involved in cleft palate induction, as exogenous arachidonic acid injected into pregnant rats and mice at the same time as glucocorticoids reduces the teratogenic potency of the steroids and indomethacin, and inhibitor of cyclooxygenase, blocks the corrective action of arachidonic acid. Glucocorticoids and phenytoin cause a delay in shelf elevation, and this delay is promoted by fetal membranes and the tongue. However, the cells of the medial edge epithelium are programmed to die whether contact is made with the apposing shelf or not. Glucocorticoids and phenytoin interfere with this programmed cell death, and this interference by both drugs seems to be a glucocorticoid receptor mediated event, to require protein synthesis and to be related to arachidonic acid release.
糖皮质激素和苯妥英钠导致腭裂是一个复杂的发育程序受到干扰的过程，该发育程序涉及许多遗传和生化过程。H-2组织相容性区域包含影响对糖皮质激素和苯妥英钠诱导腭裂易感性的基因；在包括母体和胚胎腭、成年胸腺和肺在内的多种组织中的糖皮质激素受体水平；以及糖皮质激素和苯妥英钠对胸腺细胞中前列腺素和血栓素产生的抑制程度。与第二条染色体上的一个次要组织相容性位点（H-3）相连的基因也影响对糖皮质激素和苯妥英钠诱导腭裂的易感性。苯妥英钠是糖皮质激素受体的一种替代配体，影响前列腺素和/或血栓素的产生。糖皮质激素诱导腭裂的能力与其抗炎效力相关。糖皮质激素的至少一些抗炎作用可以通过抑制前列腺素和/或血栓素释放来解释，而这又可能是由于抑制了磷脂中花生四烯酸的释放所致。腭裂诱导可能涉及类似机制，因为在给怀孕大鼠和小鼠注射糖皮质激素的同时注射外源性花生四烯酸可降低类固醇和吲哚美辛（一种环氧化酶抑制剂）的致畸效力，且吲哚美辛可阻断花生四烯酸的纠正作用。糖皮质激素和苯妥英钠会导致腭架抬高延迟，而胎膜和舌头会加剧这种延迟。然而，无论内侧边缘上皮细胞是否与相对的腭架接触，其细胞都被编程为死亡。糖皮质激素和苯妥英钠会干扰这种程序性细胞死亡，而且这两种药物的这种干扰似乎是由糖皮质激素受体介导的事件，需要蛋白质合成且与花生四烯酸释放有关。
