Cyclopamine

Warning

H341 (88.6%): Suspected of causing genetic defects [Warning Germ cell mutagenicity]

P203, P280, P318, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 44 reports by companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

IThe steroidal alkaloid cyclopamine was isolated from the plant Veratrum californicum in the late 1960's and identified as the teratogen responsible for craniofacial birth defects including cyclops in the offspring of sheep grazing on mountain ranges in the western United States. Cyclopamine inhibits the hedgehog (Hh) signaling pathway, which plays a critical role in embryonic development. Also, aberrant Hh signaling has been implicated in several types of cancer, and inhibitors of the Hh signaling pathway, including cyclopamine derivatives, have been targeted as potential treatments for certain cancers and other diseases associated with the Hh signaling pathway.

Cyclopamine, a steroidal alkaloid, is found in the corn lily (Veratrum californicum). Several species of the Veratrum genus are associated with toxicity in humans and animals. The principal toxins are steroid alkaloids, and they act by increasing the permeability of the sodium channels of nerve cells, causing them to fire continuously. The increased stimulation results in a reflex that causes the Bezold-Jarisch reflex (hypotension, bradycardia and apnea). Various Veratrum extracts had been marketed as antihypertensive drugs, but were withdrawn from the market because of a narrow therapeutic index. Following the ingestion of Veratrum alkaloids, the expected signs and symptoms include vomiting and abdominal pain, followed by cardiovascular effects such as bradycardia, hypotension, cardiac conduction abnormalities, and death. Teratogenic effects may occur to the fetuses of animals that have grazed on Veratrum californicum. The onset of symptoms occurs between 30 minutes and four hours, and the duration of the illness can range from one to 10 days. Treatment consists of supportive care, with an emphasis on hemodynamic stability with fluid replacement, atropine and vasopressors. With prompt supportive care, patients typically make a full recovery within 24 hours.

A NUMBER OF VERATRUM ALKALOIDS WERE TESTED IN PREGNANT SHEEP FOR TERATOGENICITY. THE COMPOUNDS JERVINE, CYCLOPAMINE...AND CYCLOPOSINE...PRODUCED DEFORMITIES SIMILAR TO NATURAL CASES. THE 3 TERATOGENIC COMPOUNDS ARE CLOSELY RELATED STEROIDAL FURANOPIPERIDINES, BUT CYCLOPAMINE IS THE TERATOGEN OF NATURAL IMPORTANCE BECAUSE OF PLANT CONCN. CLOSELY RELATED COMPD DEVOID OF THE FURAN RING DID NOT PRODUCE CYCLOPIA IN SHEEP, SUGGESTING THAT AN INTACT FURAN RING WAS REQUIRED FOR ACTIVITY, PERHAPS CONFERRING SOME ESSENTIAL CONFIGURATION ON THE MOLECULE.

The Veratrum genus is composed of plants containing a diverse set of steroidal alkaloids. Veratrum plant material has been utilized for centuries as herbal medicines. The alkaloids have such a low therapeutic index that they are not used in modern medicine. Veratrum parviflorum, commonly known as Appalachian bunchflower, contains the steroidal alkaloids cyclopamine along with other toxic alkaloids such as jervine, veratramine, veratridine, and verazine. This publication is about an inadvertent ingestion of Veratrum parviflorum by hikers in Georgia. It allowed for the detection, and in several instances identification of alkaloids from the plant, and correlated their presence within patient blood and breast milk specimens. Eight patients, three male and five female, presented in the spring of 2020 and 2021 with symptoms requiring emergent medical attention after ingestion of Veratrum parviflorum. All patients believed the plants to be a local native species of wild leek, Allium tricoccum, locally known as ramps. Plants were identified using photographs as well as fresh and cooked plant material provided by patients, in consultation with botanists at the University of Georgia Herbarium. Veratrum parviflorum plant material, and patient serum and breast milk were analyzed by high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (HPLC-QTOF) to identify steroidal alkaloids.The Veratrum parviflorum extract was confirmed to contain cyclopamine, veratramine, jervine, and muldamine. Two out of the eight patients had detectable concentrations of Veratrum alkaloids. Of the alkaloids identified in the plant, cyclopamine and jervine were detected within patient serum, and cyclopamine and veratramine were observed to be present in breast milk. This is the second report of V. parviflorum poisoning and reports for the first time the presence of muldamine and jervine within veratrum parviflorum. Also, this work provided the first identification of Veratrum alkaloids in breast milk. The findings presented herein add to literature record causative agents contributing to the toxicity of veratrum parviflorum when ingested and potential for secondary poisoning through breastfeeding. Veratrum parviflorum toxicity was observed to cause nausea, vomiting, hypotension, bradycardia, abdominal pain, light-headedness, blurred vision, and tingling in the arms. Patients experiencing mild symptoms improved with supportive care, IV fluids, and antiemetics, but hemodynamically unstable patients required atropine and vasopressors. This study demonstrated that more lipophilic Veratrum alkaloids can be passed along in breast milk.