Senecionine

Practically insol in water; freely sol in chloroform; slightly sol in alc, ether

In water, 8.5X10+4 mg/L @ 25 °C /Estimated/

Danger

H301 (97.6%): Toxic if swallowed [Danger Acute toxicity, oral]

P264, P270, P301+P316, P321, P330, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 41 reports by companies from 4 notifications to the ECHA C&L Inventory.

Emergency treatment: Plants- pyrrolizidine alkaloids; Pyrrolizidine alkaloids (PAs) cause veno-occlusive liver disease. Diagnosis is difficult because symptoms may be delayed for days or weeks. After drinking herbal tea or eating plants contaminated with seeds of PA plants, symptoms may include vomiting, abdominal pain, hepatomegaly, and later cirrhosis and ascites. Jaundice may be present. Children may appear to have Reye's syndrome. [HSDB] Teas containing PAs include coltsfoot, comfrey, gordolobo, groundsel, mate, tansy ragwort, and T'u-san-chi. The teas may be prescribed as herbal remedies for anxiety or amenorrhea. The alkaloid is concentrated in the root of the plants. As little as 85 mg may be toxic. [Haddad, p. 1082]

REVIEW OF NATURALLY OCCURRING CARCINOGENS OF PLANT ORIGIN INCLUDING PYRROLIZIDINE ALKALOIDS.[HIRONO I; NATURAL CARCINOGENIC PRODUCTS OF PLANT ORIGIN; CRIT REV TOXICOL 8 (3): 235-66 (1981)]

REVIEW ON THE PLANT SOURCES OF HEPATOTOXIC PYRROLIZIDINE ALKALOIDS.[SMITH LW, CULVENOR C CJ; PLANT SOURCES OF HEPATO TOXIC PYRROLIZIDINE ALKALOIDS; J NAT PROD (LLOYDIA) 44 (2): 129-52 (1981)]

We have purified three P450s from the liver of the phenobarbital (PB)-treated guinea pig in order to evaluate the role of these enzymes in pyrrolizidine alkaloid (PA) metabolism. PB treatment of guinea pig increased the hepatic microsomal conversion of the PA senecionine (SN) to the pyrrolic metabolite (+/-)6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP), an activation product, and SN N-oxide, a detoxification product by 224 and 70% respectively. ... . A second purified guinea pig P450, a 2C-type isoform (M(r) = 56,496 by MALDI-TOF mass spectrometry), produced SN N-oxide from SN at the rate of 13.3 min-1 but catalyzed little DHP formation. The third guinea pig P450, an apparent 3A type (M(r) = 54-56,000 by SDS-PAGE), lost its catalytic activity towards SN during the final purification process.

(14)C-senecionine was injected into balb/c mice and was rapidly excreted in the urine and feces (84% or greater) within 16 hr. The liver contained over 1.5% of the dose at 16 hr. A small amt, 0.04%, of the dose was transferred into the milk in 16 hr; the majority of radioactivity was found in the Skim-milk fraction.

Lactating rats admin (3)H-necic acid-labelled senecionine excreted within 3 hr approx 0.08% of the radioactivity in the milk.

Senecionine is classified as a pyrrolizidine alkaloid (PA). Unsaturated pyrrolizidine alkaloids are hepatotoxic, that is, damaging to the liver. PAs also cause hepatic veno-occlusive disease and liver cancer. PAs are tumorigenic. Disease associated with consumption of PAs is known as pyrrolizidine alkaloidosis. (Wikipedia) The pyrrolizidine alkaloid senecionine has been shown to produce an increase in cytosolic free Ca2+ concentration in isolated hepatocytes that correlated with an increase in cellular toxicity. The cytotoxicity was greater in the absence of extracellular Ca2+ than in its presence, suggesting that alterations in intracellular Ca2+ distribution, and not an influx of extracellular Ca2+, were responsible for the senecionine-induced hepatotoxicity. Senecionine has been shown to be hepatotoxic, genotoxic, and cytotoxic. Senecionine has been shown to produce peroxidation of membrane lipids in a dose-related manner in isolated rat hepatocytes. Alterations in intracellular Ca2+ concentration also were examined as a possible primary mechanism of cellular toxicity. (A15422) Substantial research has revealed that senecionine-induced hepatotoxicity is associated with lipid peroxidation, intracellular Ca2+ alteration, and intercellular glutathione depletion. (A15423)

Senecionine is one of the alkaloids present in honey produced from the nectar of tansy ragwort (Senecio jacobaea).

SENECIONINE WAS ISOLATED FROM BRACHYGLOTTIS REPANDA.

SENECIONINE WAS ISOLATED FROM BULGARIAN VARIETIES OF SENECIO ERUCIFOLIUS.

The isolation and identification, by spectroscopic analysis, of senecionine from Senecio inaequidens are reported.

For more Natural Pollution Sources (Complete) data for SENECIONINE (10 total), please visit the HSDB record page.

/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/

/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/ In man, poisoning is manifested as acute veno-occlusive disease, leading to hepatomegaly, ascites, massive pleural effusion, and in many cases progressing to cirrhosis.

/SIGNS AND SYMPTOMS/ In humans, symptoms are generally acute in onset and are characterized by upper abdominal discomfort that develops rapidly and progresses to swelling of abdomen resulting in so-called veno-occlusive disease. The disease progresses rapidly and the mortality is high. /pyrrolizidine alkaloids/

/LABORATORY ANIMALS: Acute Exposure/ Senecionine (42.6 mg/kg) given sc to rats increased the liver glutathione (GSH) content in 12 hr, and decreased total plasma proteins and increased GSH in erythrocytes and blood bilirubin levels after 24-36 hr. The hematocrit was not affected.

/LABORATORY ANIMALS: Acute Exposure/ Rats given for several wk an extract from a commercial prepn of senecio vulgaris, which contained senecionine showed loss of body wt and hepatic centrilobular congestion.

/LABORATORY ANIMALS: Acute Exposure/ Single ip injections of pyrrolizidine alkaloids ranging from 0.025 to 3.2 mmol/kg were admin to 2 wk-old rats. Senecionine was lethal at 0.1 mm/kg. They caused megalocytosis and consistently inhibitied cell division.

/LABORATORY ANIMALS: Acute Exposure/ The activities of glutamic pyruvic transaminase, glutamic oxaloacetic transaminase, lactate dehydrogenase and that of their isoenzymes were studied in rat plasma during acute intoxication with the pyrrolizidine alkaloid senecionine. An increase in enzyme activity, which was time dependent, reached a max 48 hr after sc admin of senecionine. Higher activities were noted in female rats.

For more Non-Human Toxicity Excerpts (Complete) data for SENECIONINE (17 total), please visit the HSDB record page.

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/

LD50 Hamster iv 611 mg/kg

LD50 Rat iv 41.2 mg/kg

LD50 Mouse iv 64 mg/kg

LD50 Rat ip 50 mg/kg /from table/

On the isolated guinea pig ileum preparation, platyphylline, supinine, heleurine, and cynaustraline were more potent in antagonizing responses to acetylcholine (ii). Their anticholinergic activity appeared to involve a competitive mechanism. The pyrrolizidine alkaloids had no appreciable activity as antagonists of (ii) in the isolated toad rectus abdominis preparation.

The activation of the alkaloids by mixed-function oxidases leads to pyrrolic dehydro-alkaloids which are reactive alkylating agents. The liver necrosis results from binding of the metabolites with the liver cell. Some metabolites are released into the circulation and are believed to pass beyond the liver to the lung causing vascular lesions. The pyrrolic metabolites are cytotoxic and act on the hepatocytes and on the endothelium of blood vessels of the liver and lung. /pyrrolizidine alkaloids/

Senecionine admin showed spasmolytic activity, primarily on intestinal smooth muscles.

Within a few hours, only a relatively small proportion of the administered dose remains in the body. Much of this is in the form of metabolites bound to tissue contents. A pyrrolizidine N-oxide disappeared from the serum after IV administration in animals, with initial half-lives of 3 to 20 minutes. /pyrrolizidine alkaloids/

Using microsomes from livers of phenobarbitone-pretreated male rats, pyrrolizidine alkaloids tested were metabolized to n-oxides and pyrroles.

The in vitro mouse hepatic microsomal metabolism of the macrocyclic pyrrolizidine alkaloid senecionine was studied. Senecic acid, senecionine n-oxide and 19-hydroxysenecionine, a new metabolite, were isolated from the microsomal enzyme system of balb/c mice.

The toxic pyrrolizidine alkaloids, such as senecionine, are cyclic arylamines that are dehydrogenated by cytochrome P450 (CYP3A4) to the corresponding pyrroles. Pyrroles themselves are nucleophiles, but electrophiles are generated through the loss of substituents on the pyrrolizidine nucleus... .

In animals, the major metabolic routes of pyrrolizidine alkaloids are: (a) hydrolysis of the ester groups; (b) N-oxidation; and (c) dehydrogenation of the pyrrolizidine nucleus to pyrrolic derivatives. Routes (a) and (b) are believed to be detoxification mechanisms. Route (c) leads to toxic metabolites. Route (a) occurs in liver and blood; routes (b) and (c) are brought about in the liver by the microsomal mixed function oxidase system. /pyrrolizidine alkaloids/

For more Metabolism/Metabolites (Complete) data for SENECIONINE (7 total), please visit the HSDB record page.

In animal studies highest concentrations were found in the liver, lungs, kidneys and spleen. /pyrrolizidine alkaloids/

Blood levels of senecionine in rats given 0.1 LD50 ip were determined. The levels were 0.38, 0.32, and 0.14 mg/litre at 0.5, 1, and 2 h after injection, respectively.

...Senecionine... /was/ studied regarding the distribution, excretion, transfer into milk, and covalent binding to hepatic macromolecules in BALB/c mice. After injection, radioactivity was rapidly excreted in the urine and feces (84% or greater) within 16 hr. The liver contained over 1.5% of the dose at 16 hr. A small amount, 0.04%, of the dose was transferred into the milk in 16 hr; the majority of radioactivity was found in the skim-milk fraction, suggesting that the PA's were transferred to the milk as water-soluble metabolites. ...The binding to calf thymus DNA and microsomal macromolecules was measured in vitro. The binding was diminished in the absence of O2 or a NADPH-generating system or by boiling the microsomes.

...Following intravenous administration of [14C]SEN (60 mg/kg, 10 microCi/kg), bile, urine and blood were collected over a 7-hr period. Of the total administered radioactivity, 44% and 43% were excreted in the bile and urine, respectively. Using mass spectroscopy, senecionine N-oxide (SENNOX) was identified as the major metabolite in bile (52% of 44%) and urine (30% of 43%). For the total 7 hr, <5% in bile and 18% in urine was excreted as parent alkaloid.

Hepatotoxic alkaloid from plants of the Senecio species; [Merck Index] Used as a folk remedy (uterine stimulant and treatment of diabetes mellitus, hemorrhage, and high blood pressure); [HSDB]

Senecio herb is used /as a folk remedy/ for diabetes mellitus, hemorrhage, high blood pressure, for spasms, and as a uterine stimulant.