Steroidal Alkaloid Teratogens: Molecular Probes for Investigation of Craniofacial Malformations

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Abstract
Holoprosencephaly, a malformation sequence that results from impaired midline cleavage of the embryonic forebrain, is expressed as a spectrum of craniofacial anomalies of which cyclopia is the most severe. The Veratrum alkaloids are the most prominent of the teratogenic agents known to induce holoprosencephaly in mammals. Jervine and 11-deoxojervine (cyclopamine) are potent steroidal alkaloid teratogens from Veratrum californicum that are responsible for inducing cyclopic malformations in sheep. Extensive structure-terata investigations of jervanes, solanidanes, and spirosolanes have shown that teratogenicity induced upon oral administration of all three structural types is significantly higher if the C-5, C-6 bond is unsaturated. Research in progress on the pathogenesis of holoprosencephalic malformations in both hamsters and humans offers the potential to provide information on the receptors involved in the expressions of these craniofacial syndromes. A clearer understanding of steroidal alkaloid-induced teratogenesis will emerge when appropriate receptor sites are revealed with which teratogenic alkaloids of slightly different structure can interact.