Cyclopamine and related steroidal alkaloid teratogens: Their occurrence, structural relationship, and biologic effects

Abstract

A spontaneous congenital deformity is produced in lambs whose dams consume Veratrum californicum on the 14th day of gestation. The deformity is generally expressed as cyclopia, cebocephaly, anophthalmia, or microphthalmia. This teratogenic effect is produced by certain steroidal alkaloid teratogens from the plant - most notably the compound cyclopamine. Cyclopamine is a C-nor-D-homo steroid with fused furanopiperidine rings E and F at right angles to the plane of the steroid because of spiro attachment at C-17 of the steroid. Among veratrum alkaloids, only those with an intact furan ring E were teratogenic in sheep, whereas those in which the peperidine ring is not rigidly positioned at right angles to the steroid were not. Many ruminants and laboratory animals are susceptible to the teratogen. It has wide species and tissue specificity and appears to have a direct effect on the embryo, not as a consequence of metabolic alteration of its structure nor as an indirect effect through a maternal influence. Other plant sources, notably potatoes, tomatoes, and eggplant contain related spirosolane steroidal alkaloids. Among naturally occurring spirosolanes, solasodine is teratogenic in hamsters, but neither tomatidine not diosgenin, the non-nitrogen containing analog of solasodine, is teratogenic. Results of these and other studies suggest that a basic nitrogen positioned alpha with respect to the steroidal plane and at appropriate distance beyond the D ring confers the teratogenicity on the molecule. Potato sprouts with high alkaloid content are teratogenic in hamsters, but tubers and peels are not.

Congenital Abnormalities in Production Animals

“…5), or synophthalmia, in which both eyes are joined in one frontal orbit (see Fig. 2A in the article by Middleton elsewhere in this issue), is part of a wide range of craniofacial abnormalities arising from the teratogenic action of the alkaloidal steroid cyclopamine, 19,20 but with a relatively narrow window of activity, both temporally and dose-related. 21 Cyclopamine inhibits the hedgehog signal transduction pathway.…”

Common critical pathways in embryogenesis and cancer

“…Environmental toxins can target another signalling component of the hedgehog/Gli pathway, Smoothened (SMOH). Exposure to the teratogenic alkaloid cyclopamine a hedgehog pathway antagonist in the plant Veratrum californicum has been found to cause a congenital holoprosencephalopathy in studies on livestock [30,31]. This arises through inhibition of the Shh signalling pathway at the level of the smoothened receptor (SMOH).…”

Greased hedgehogs: New links between hedgehog signaling and cholesterol metabolism

“…(77) Vitamin D-deficient individuals do not show increased cancer susceptibility, as would be expected if Smo were overactive, (78) and vitamin D may even have an antiproliferative and proapoptotic effect on cancer cells. (79) Also, cattle that feed on vitamin D3-laden South American egg plants, Solanum malacoxylon, develop pathologic calcification (80) but do not show any developmental malformations that would resemble the Hh-related defects seen so strikingly in Veratrum-poisoned sheep, (81) in which Smo is overinhibited by the cyclopamine contained in the plants. (82,83) This difference could, however, also be explained by differences in pharmacokinetics of the two compounds.…”