Overexpression of p53 explains isotretinoin's teratogenicity.

The precise molecular basis of retinoid embryopathy is yet unknown. This hypothesis predicts that isotretinoin (13-cis retinoic acid), the prodrug of all-trans retinoic acid (ATRA), exaggerates neural crest cell (NCC) apoptosis via upregulation of the pro-apoptotic transcription factor p53, the guardian of the genome. Increased p53 signalling is associated with Treacher Collins-, CHARGE- and fetal alcohol syndrome, which exhibit dysmorphic craniofacial features resembling retinoid embryopathy. In addition, developmental studies of NCC homeostasis in the zebrafish support the pivotal role of p53. Translational evidence implies that isotretinoin-stimulated overactivation of p53 during embryogenesis represents the molecular basis of isotretinoin's teratogenicity.