Jacobine

351.4 g/mol

351.39

Colorless plates

88.6 Ų

log Kow = -0.78 @ 25 °C /Estimated/

228 °C

Sol in chloroform; sparingly sol in ethanol, water and ether|In water, 1.5X10+5 mg/L @ 25 °C /Estimated/

For long periods, it is best stored under nitrogen at -15 °C.

9.3X10-13 mm Hg @ 25 °C /Estimated/

Henry's Law constant = 5.6X10-13 atm-cu m/mol @ 25 °C /Estimated/

READILY HYDROLYZED WITH ALKALI; REACTS WITH HYDROCHLORIC ACID TO FORM THE CHLORHYDRIN, JACONINE|Hydroxyl radical reaction rate constant = 1.3X10-10 cu cm/molec-sec @ 25 °C /Estimated/

Stable at room temp in closed containers; slightly volatile

Readily hydrolysed with alkali; reacts with hydrochloric acid to form the chlorhydrin, jaconine.

REVIEW OF CARCINOGENIC PRODUCTS OF PYRROLIZIDINE ALKALOIDS; INCLUDES JACOBINE.[HIRONO I; NATURAL CARCINOGENIC PRODUCTS OF PLANT ORIGIN; CRIT REV TOXICOL 8(3) 235 (1981)]|PLANT SOURCES OF HEPATOTOXIC PYRROLIZIDINE ALKALOIDS.[SMITH LW, CULVENOR C CJ; PLANT SOURCES OF HEPATO TOXIC PYRROLIZIDINE ALKALOIDS; J NAT PROD (LLOYDIA) 44(2) 129 (1981)]|A GENERAL REVIEW ON TOXICITY OF PYRROLIZIDINE ALKALOIDS.[MCLEAN EW; THE TOXIC ACTIONS OF PYRROLIZIDINE (SENECIO) ALKALOIDS; PHARMACOL REVIEW 22(4) 429 (1970)]|A REVIEW ON MECHANISMS OF ACTION OF PYRROLIZIDINE ALKALOIDS.[MATTOCKS AR; MECHANISMS OF PYRROLIZIDINE ALKALOID TOXICITY; PHARMACOLOGY AND THE FUTURE OF MAN. PROC 5TH INT CONGR PHARMACOLOGY, SAN FRANCISCO 2: 114 (1972)]|For more Special Reports (Complete) data for JACOBINE (6 total), please visit the HSDB record page.

Zinc, 72 umol/kg as zinc chloride, was administered ip for 3 consecutive days, followed 16 hours after the last dose by a single ip injection of purified mixed pyrrolizidine alkaloids (pa's) (80, 120, or 160 mg/kg) obtained from tansy ragwort. A 7-fold increase in plasma glutamic-oxaloacetic transaminase and 12-fold increase in glutamic-pyruvic transaminase after pa's (120 mg/kg) were reduced to 2.4 and 2.1-fold, respectively by zinc pretreatment. The pa-induced liver necrosis was either reduced in severity or abolished by zinc when the pa dose was 80 or 120 mg/kg. These results suggest a protective effect of zinc against pa hepatotoxicity. The effect was associated with a marked increase in liver metallothionein and a significant decrease in hepatic cytochrome P-450 content, aminopyrine n-demethylase activity, and in vitro microsomal conversion of the pa's to pyrroles.|Diets containing 0.75% butylated hydroxyanisole (BHA), 0.25% ethoxyquin, or 1% cysteine were fed to mice for 10 days before the ip administration of mixed pyrrolizidine alkaloids from Senecio jacobaea, 280 mg/kg. Without the dietary antioxidants, the pa's produced 100% mortality in 24 hours. The bha and ethoxyquin diets were completely and partially protective, respectively, against the pa-induced lethality. The deaths were associated with severe hemorrhagic lesions in liver with or without hepatocytic necrosis. Both bha and ethoxyquin significantly reduced the incidence of the hemorrhagic lesions but not the necrotic lesions in liver.|In control animals, ip administration of a single dose of mixed pyrrolizidine alkaloids, 160 mg/kg, produced marked fibrosis, biliary hyperplasia, megalocytosis, necrosis and calcification in liver 8 weeks post injection. In contrast, consumption of 0.75% butylated hydroxyanisole (bha) diet 10 days before and 14 days after pyrrolizidine alkaloid administration reduced the incidence and/or completely prevented the occurrence of these pathological changes. Similar treatment with 1% cysteine, however, only reduced the severity of the hepatic lesions.|Young male rats were fed diets containing 0 or 5% dried tansy ragwort tops and 0 or 50 ug/g copper as copper sulfate for 5 weeks. Consumption of diets containing 5% tansy ragwort alone produced a significant reduction in weight gain accompanied by a 122% increase in plasma aspartate aminotransferase, a 106% increase in alkaline phosphatase activity, and a 152% increase in alanine aminotransferase activity, compared to pair-fed controls. When copper was added to the diet, the activities of both plasma aspartate aminotransferase and alanine aminotransferase were increased by more than 350%. Plasma alkaline phosphatase activity was also further enhanced by dietary copper in the tansy ragwort-fed animals but to a lower extent. Supplementary copper alone or a reduction in food intake had no significant effect on any of the enzyme activities. The results suggest that copper potentiates the hepatotoxic effects of tansy ragwort in rats.

LD50 Mouse iv 77 mg/kg|LD50 Rat ip 138 mg/kg/3 days, female (95% CONFIDENCE LIMIT, 117-149 MG/KG)

...OCCURS IN...SENECIO SPECIES (FAMILY COMPOSITAE): S BRASILIENSIS DC, S CINERARIA DC, S JACOBAEA L & S PALUDOSUS L. S JACOBAEA IS A COMMON WEED IN TEMPERATE REGIONS.|THE HEPATOTOXIC ALKALOIDS KNOWN TO OCCUR IN TANSY RAGWORT (S JACOBAEA) ARE ALSO PRESENT IN HONEY PRODUCED FROM THE NECTAR OF THIS SPECIES. THESE ALKALOIDS INCLUDE JACOBINE.

The data suggest that consumption of milk from goats fed Senecio jacobaea produces a selective alteration of the activities of hepatic drug-metabolizing enzymes.

Excretion of pyrrolizidine alkaloids (pa's) in diet of rabbits was not affected by the addition of copper and zinc to the diet. Isolated pa's from Senecio jacobaea were found to be readily transferred across the mucosa of isolated everted sacs of jejunum and ileum in vitro against a concentration gradient. These results suggest that the effects of dietary Senecio jacobaea on alterations in mineral metabolism are not due to changes in GI mineral absorption. In addition, it appears that the resistance of rabbits to dietary Senecio jacobaea intoxication is not caused by low GI absorption of pyrrolizidine alkaloids, but rather by efficient urinary elimination.

In general, the hepatotoxic pyrrolidine alkaloids are metabolized in rat liver to give hydrolysis products, n-oxides and dehydropyrrolizidine (pyrrolic) deriv. The latter group appears on current evidence to mediate most of toxic reactions of alkaloids. These pyrrolic deriv are produced by mixed-function oxidases of liver cells. Initial product formed from alkaloids that are esters of...retronecine (eg, jacobine...) is very probably the dehydroalkaloid. Dehydroalkaloids are highly reactive alkylating agents which react immediately with cell constituents to give soluble or bound secondary metabolites or which hydrolyze to dehydroaminoalcohol. /pyrrolizidine alkaloids/|The effect of prolonged phenobarbital (pb) administration on the toxicity of Senecio jacobaea (sj) was studied in sheep. Results suggested that mixed-function oxidase induction by pb does not increase the susceptibility of sheep to sj intoxication. Sheep possess a high activity of hepatic microsomal epoxide hydrolase which could account for their resistance to sj intoxication.|Comparison is made of the alkylating activities of a series of semi-synthetic pyrrole esters and pyrrole derivatives of pyrrolizidine alkaloids under pseudo-first-order reaction conditions. Data for alkylation by jacobine pyrrole (a reactive metabolite of jacobine) fit a simple first-order rate expression for product formation. The large increase in reaction rate for jacobine pyrrole is suggestive of an electronic field effect due to the epoxide ring in proximity to the C-7 ester moiety.

Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/|Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/|Presentation depends on the active toxic agent. In most cases, vomiting, abdominal pain, and diarrhea occur within 60 to 90 minutes of significant ingestion. With some toxins, severe gastroenteritis may result in massive fluid and electrolyte loss. ... Maintain open airway and assist ventilation if necessary. Administer supplemental oxygen. Treat coma, seizures, arrhythmias, and hypotension if they occur. Replace fluid loss caused by gastroenteritis with intravenous crystalloid solutions. ... Administer activated charcoal if available ... Gastric emptying is not necessary if activated charcoal is given promptly. /Plants and Herbal Medicines: Group 1/

/HUMAN EXPOSURE STUDIES/ The hepatotoxic alkaloids known to occur in tansy ragwort (S. jacobaea) are also present in honey produced from the nectar of this species. These alkaloids, which include jacobine, are potentially carcinogenic, mutagenic, and teratogenic and may pose health hazards to the human consumer.|/HUMAN EXPOSURE STUDIES/ Human consumption... occurs from Symphytum and Senecio species in some herbal preparations, such as "comfrey tea" or "groundsel tea". /Pyrrolizidine alkaloids from Senecio species/|/HUMAN EXPOSURE STUDIES/ The two main sources of pyrrolizidine alkaloid poisoning reported in human beings are the consumption of cereal grain contaminated by weeds containing the alkaloids and the use of alkaloid-containing herbs for medicinal and dietary purposes. ...Three of the largest outbreaks of the disease have been reported from South Asia, two from the same site in central India and one from North-West Afghanistan. The first Indian outbreak... occurred in a group of 5 tribal villages in central India in 1972-73. ...Out of a total population of 2,060 in these villages, 71 households with 366 members were investigated. Among these, 39 cases had developed and 19 had died before commencement of the investigations. The incidence rate was 1.1% and the case fatality rate was 50%. All cases occurred among 20 households. In many households, several members were affected. In one household, 4 out of 5 cases died. ...The etiological factor of this outbreak was not established, though dietary contamination with pyrrolizidine alkaloids was considered. A second outbreak occurred at the same site in 1975... . A total population of 486 was affected, 67 cases were reported, of whom 28 (46%) had died. There was a strong family history... . In a later survey, 108 patients were studied and the mortality rate was estimated to be 63%. This time the etiological factor was identified as the plant Crotalaria nana Burm, which had been growing in the fields of millet (Panicum miliare), their staple food crop. The seeds of this plant became mixed with the cereal grain during harvesting. The toxic seeds contained pyrrolizidine alkaloids that were identified as a macrocyclic ester closely similar to monocrotaline. The total alkaloid content was estimated to be 5.3 g/kg of seed, expressed as monocrotaline. The levels of contamination of the millet with seeds were reported to be 0-3.4 g/kg in the unaffected and 0-19 g/kg in the affected households... . /Pyrrolizidine alkaloids/|/HUMAN EXPOSURE STUDIES/ The largest outbreak reported to date occurred in the Gulran district of Herat Province in northwest Afghanistan, close to the border of the USSR. ...The outbreak, was estimated to have affected a population of approximately 35,000 in 98 villages. Examination of 7,200 inhabitants of the affected villages showed evidence of disease in 22.6%, which was more serious in 15%. Thus, it was estimated that approximately 8,000 subjects suffered from the disease including 5,000 who were seriously affected. All age groups were affected, but 46% of subjects were below 14 years of age. However, no sign of disease was found in children below 2 years of age. A detailed report concerning the pathological material obtained from 14 liver biopsies and 8 autopsies was made... /although/ the time interval between the onset of symptoms and the biopsy/autopsy was not indicated. Pathological findings were characteristic, ranging from acute disease with characteristic veno-occlusion to non-portal cirrhosis, which was observed in 5 of the above 22 cases. The outbreak was ascribed to massive contamination of wheat, the staple food crop, following 2 years of drought, with the seeds of Heliotropium popovii H. Riedl subsp. gillianum H. Riedl, which had been growing profusely among the wheat crop. The seeds contained pyrrolizidine alkaloids at concentrations reported by 2 laboratories to be 7.2 and 13.2-14.9 g/kg, identified mainly as the N-oxide of heliotrine (74%)..., and one or two other compounds similar in character to lasiocarpine. Samples of wheat from several villages contained an average of 40 seeds/kg, i.e., 0.03% by weight. It was estimated that an adult consumed at least 700 g flour/day, containing approximately 2 mg alkaloid (based on a mean of the seed analyses). /Pyrrolizidine alkaloids/

jacobine

An alkaloid isolated from ... /Senecio/ jacobaea.

A PROCEDURE IS DESCRIBED FOR THE ELECTRON CAPTURE GAS CHROMATOGRAPHY DETERMINATION OF PYRROLIZIDINE ALKALOIDS IN MILK. RECOVERIES OF 80-90% WERE OBTAINED FROM CONTROL MILK SAMPLES FORTIFIED WITH 0.2-1.0 PPM JACOBINE. PYRROLIZIDINE ALKALOIDS WERE DETERMINED IN THE MILK FROM GOATS FED 1% OF THEIR BODY WEIGHT/DAY OF DRIED FLOWERING TOPS OF SENECIO JACOBAEA (TANSY RAGWORT). THE CONCENTRATION RANGE OF ALKALOIDS FOUND IN MILK WAS 0.33 TO 0.81 PPM.|A METHOD USING A REVERSED-PHASE STYRENE-DIVINYLBENZENE RESIN HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY COLUMN ON 3 1.00 G SAMPLES OF S JACOBAEA EXTRACTED JACOBINE WITH 10-30% ACETONITRILE-NH4OH GRADIENT. THE AVERAGE VALUE OF JACOBINE IN MUG/G DRY WEIGHT WAS 1019.|A GC-MS ANALYSIS OF SENECIO ALPINUS AND OF HAY AND SILAGE CONTAINING THIS PLANT REVEALED THE PRESENCE OF 9 DIFFERENT HEPATOTOXIC PYRROLIZIDINE ALKALOIDS WITH JACOBINE AS A MINOR CONSTITUENT.|THE ANALYSIS OF PLANT MATERIAL FOR PYRROLIZIDINE ALKALOIDS IS BASED ON A GENERAL PROCEDURE FOR EXTRACTION OF THE TERTIARY BASE ALKALOIDS BEFORE AND AFTER REDUCTION OF THE ALKALOID N-OXIDES WHICH ARE ALSO USUALLY PRESENT. THE DIFFERENCE IN THE TWO RESULTS IS AN APPROXIMATE MEASURE OF THE N-OXIDE CONTENT OF THE PLANT MATERIAL. THE LEVELS OF BOTH TERTIARY BASE AND N-OXIDE FORMS OF THE ALKALOID ARE RELEVANT TO AN EVALUATION OF THE TOXICITY OF THE PLANT MATERIAL. THE INDIVIDUAL BASES ARE SEPARATED AND ESTIMATED BY PARTITION CHROMATOGRAPHY OR THIN-LAYER, PAPER OR GAS CHROMATOGRAPHY. /PYRROLIZIDINE ALKALOIDS/|For more Analytic Laboratory Methods (Complete) data for JACOBINE (6 total), please visit the HSDB record page.

Pyrrolizidine alkaloids may be estimated in animal tissues and fluids by removing protein, chromatographing on Florisil and estimating colorimetrically with methyl orange. /Pyrrolizidine Alkaloids/