Chapter 10. Biochemical Mechanism of Glucocorticoid-and Phenytoin-Induced Cleft Palate

Abstract

The production of cleft palate by glucocorticoids and phenytoin is a complicated interference in a complex developmental program involving many genetic and biochemical processes. The H-2 histocompatibility region includes genes which affect (1) susceptibility to glucocorticoid- and phenytoin-induced cleft palate; (2) glucocorticoid receptor level in a variety of tissues including maternal and embryonic palates, adult thymuses, and lungs; and (3) 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, an 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 glucocorticoid receptor mediated, to require protein synthesis, and to be related to arachidonic acid release.