Jervin

Jervine's biological activity is mediated via its interaction with the 7 pass trans membrane protein smoothened. Jervine binds with and inhibits smoothened, which is an integral part of the hedgehog signaling pathways. With smoothened inhibited, the GLI1 transcription cannot be activated and hedgehog target genes cannot be transcribed. (Wikipedia) It is now known that the teratogenic effects of jervine and cyclopamine are due to their specific inhibition of vertebrate cellular responses to the Hedgehog (Hh) family of secreted growth factors. (A15438) In cultures with cyclopamine, jervine, or blocking antibody, fungiform papilla numbers doubled on the dorsal tongue with a distribution that essentially eliminated inter-papilla regions, compared with tongues in standard medium or solanidine. (A15439)

STEROIDAL ALKALOID FOUND IN VERATRUM GRANDIFLORUM (MAXIM) LOES F, V ALBUM L, V VIRIDE SOL, LILIACEAE: SAITO BULL CHEM SOC JAPAN 9, 15 (1934), CA 28, 2463 (1934); POETHKE, ARCH PHARM 275, 357, 571 (1937); 276, 170 (1938); 282, 56 (1944); SEIFERLE ET AL, J ECON ENTOMOL 35, 35 (1942); JACOBS, CRAIG, J BIOL CHEM 160, 555 (1945).

Several species of the Veratrum genus are associated with toxicity in humans and animals. The principal toxins are steroid alkaloids; some have a modified steroid template, whereas others differ in their esterified acid moieties. These alkaloids act by increasing the permeability of the sodium channels of nerve cells, causing them to fire continuously. Increased stimulation, associated with the vagal nerve results in a reflex that causes the triad of responses known as the Bezold-Jarisch reflex: hypotension, bradycardia and apnea. Clinically, various Veratrum extracts were marketed for use as antihypertensive drugs, but because of their narrow therapeutic index were withdrawn from the market. Following the ingestion of Veratrum alkaloids, expected signs and symptoms include vomiting and abdominal pain, followed by cardiovascular effects such as bradycardia, hypotension and cardiac conduction abnormalities and death. Similar symptoms arise in other mammalian species ingesting these alkaloids; teratogenic effects may occur to the fetuses of animals that have grazed on Veratrum californicum. Treatment consists of supportive care, with an emphasis on hemodynamic stability with fluid replacement, atropine and vasopressors. The onset of symptoms occurs between 30 minutes and 4 hours, and the duration of the illness can range from 1 to 10 days; however, with prompt supportive care, patients typically make a full recovery within 24 hours.

Veratrum californicum was responsible for large losses of sheep grazing high mountain ranges in central Idaho in the 1950s. Veratrum induces various birth defects including the cyclopic-type craniofacial defect (monkey-faced lambs) that is specifically induced in lambs after pregnant ewes grazed the plant on the 14th day of gestation. The steroidal alkaloids cyclopamine (1) and jervine (2) were isolated from Veratrum and shown to be primarily responsible for the malformations. Cyclopamine (1) and jervine (2) are potent teratogens that inhibit Sonic hedgehog (Shh) signaling during gastrulation-stage embryonic development, producing cyclopia and holoprosencephaly. Although losses to the sheep industry from Veratrum are now relatively infrequent, occasional incidents of toxicoses and craniofacial malformations are still reported in sheep and other species...

Golden hamster fetuses were extremely sensitive to the teratogenic action of jervine and cyclopamine, the steroidal alkaloid tetratogens from Veratrum californicum. Cebocephaly, harelip/cleft palate, exencephaly, and a cranial bled were the common deformities produced by dosing on the seventh day of gestation. Sprague-Dawley derived albino rats were susceptible to cyclopamine but not to jervine, and at an incidence very much lower than that of hamsters. Cebocephaly and microphthalmia were the common deformities. The terata were observed as a consequence of sixth to ninth-day dosings. Single-day dosings produced no terata. Swiss Webster mice were apparently resistant to the teratogens.

Eleven alkaloids obtained from Veratrum have been compared for their effects on the membrane potential and conductances of squid and crayfish giant axons. They can be classed in three groups. 1) Veratridine, cevadine and protoveratrines A and B cause the membrane to depolarize. The potency decreases in that order, and the concentrations of veratridine and cevadine required for 50% maximum depolarization are estimated to be 3.3 x 10-5 M and 3.7 x 10-3 M, respectively. The depolarization by veratridine is due primarily to a selective increase in resting sodium permeability of time membrane and is antagonized by tetrodotoxin. All of them are effective in augmenting and prolonging the negative (depolarizing) afterpotential. 2) Veratramin, eisorubijervine, muldamine (5-veratranine 3-beta, 11-alpha-diol-11-acetate) and 5-veratranine-3alpha-11alpha-diol (1x10-4) re capable of blocking the action potential with little or no depolarization. 5Veratranine-3-beta, 11-alpha-diol blocks both sodium and potassium conductance increases. 3) Cyclopamine, jervine, rubijervine and veratrosine have no effect on the resting and action potentials. Possible structure-activity relationships for these effects are discussed.

THE FALSE HELLEBORES, INCL VERATRUM ALBUM, V VIRIDE & V CALIFORNICUM, CONTAIN VARIETY OF ALKALOIDS HAVING SIMILAR PROPERTIES TO THE COMMERCIAL PRODUCT, VERATRINE... THE RHIZOME OF V ALBUM (WHITE HELLEBORE) IS SAID...TO CONTAIN...PROTOVERATRINE, TOGETHER WITH...JERVINE, RUBIJERVINE, PSEUDOJERVINE, VERATROIDINE & VERATRALBINE. SIGNS OF POISONING WITH VERATRINE & RELATED ALKALOIDS ARE SALIVATION, PURGATION, VOMITING (EVEN IN THE COW), DIURESIS, EXCITABILITY FOLLOWED BY PROSTRATION, WEAK & IRREGULAR PULSE, DEEP & SLOW RESPIRATIONS, & DEATH IN CONVULSIONS OR CONSEQUENT UPON PARALYSIS. /VERATRINE & RELATED ALKALOIDS/