STEROIDAL ALKALOID TERATOGENS - MOLECULAR PROBES FOR INVESTIGATION OFCRANIOFACIAL MALFORMATIONS

Holoprosencephaly, a malformation sequence that results from impaired midline cleavage of the embryonic forebrain, is expressed as a spectru m of craniofacial anomalies of which cyclopia is the most severe. The Veratrum alkaloids are the most prominent of the teratogenic agents kn own to induce holoprosencephaly in mammals. Jervine and 11-deoxojervin e (cyclopamine) are potent steroidal alkaloid teratogens from Veratrum californicum that are responsible for inducing cyclopic malformations in sheep. Extensive structure-terata investigations of jervanes, sola nidanes, and spirosolanes have shown that teratogenicity induced upon oral administration of all three structural types is significantly hig her if the C-5, C-6 bond is unsaturated. Research in progress on the p athogenesis of holoprosencephalic malformations in both hamsters and h umans offers the potential to provide information on the receptors inv olved in the expressions of these craniofacial syndromes. A clearer un derstanding of steroidal alkaloid-induced teratogenesis will emerge wh en appropriate receptor sites are revealed with which teratogenic alka loids of slightly different structure can interact.