About 3% of flowering plants worldwide contain pyrrolizidine alkaloids (PA), which are among the most hepatotoxic chemicals originating from plants. The majority of PAs pose serious health risks to people and cattle when consumed through plants and PA-contaminated foods, beverages, milk, honey, herbal teas, and medications [1].

The pharmacokinetics of adonifrine and Senecio following oral and intravenous injection differ significantly. Senecio and adonifrine are quickly metabolized to produce PA N-oxides and hydroxylation products of PA or its N-oxide, have a limited bioavailability, and are quickly absorbed [1]. Senecioline decreases the activities of glutathione-S-transferase, aminopyrine demethylase, and AHH but cannot increase epoxide hydratase [2]. Three of the seven mice who received twice-weekly injections of a third component, senecioline, gave birth prematurely, and all litters' pups either perished soon after birth or were stillborn [3].

Absorption, Distribution and Excretion
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.

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Metabolism / Metabolites
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.

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Biological Half-Life
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/

Toxicity Summary
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)

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Interactions
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.

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Non-Human Toxicity Values
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/

[1]. The comparative pharmacokinetics of two pyrrolizidine alkaloids, senecionine and adonifoline, and their main metabolites in rats after intravenous and oral administration by UPLC/ESIMS. Anal Bioanal Chem. 2011 Jul;401(1):275-87.

[2]. Effect of seneciphylline and senecionine on hepatic drug metabolizing enzymes in rats. J Ethnopharmacol. 1984 Dec;12(3):271-8.

[3]. Identification of senecionine and senecionine N-oxide as antifertility constituents in Senecio vulgaris. J Pharm Sci. 1988 May;77(5):461-3.

Senecionine is a pyrrolizidine alkaloid isolated from the plant species of the genus Senecio. It has a role as a plant metabolite. It is a lactone, a pyrrolizidine alkaloid and a tertiary alcohol. It is functionally related to a senecionan. It is a conjugate base of a senecionine(1+).
Senecionine has been reported in Jacobaea carniolica, Senecio rodriguezii, and other organisms with data available.
Senecionine is an organic compound with the chemical formula C18H25NO5. It is classified as a pyrrolizidine alkaloid.
See also: Petasites hybridus root (part of); Tussilago farfara flower (part of); Tussilago farfara leaf (part of).

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Mechanism of Action
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.

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

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Drug Warnings
Senecio herb contains varying amounts of toxic pyrrolizidine alkaloids (PA) which are known to have organotoxic, in particular hepatotoxic,effects
The therapeutic administration of senecio herb is not justifiable because of its insufficient or undocumented effectiveness and the presence of toxic pyrrolizidine alkaloids.

C18H35NO5

335.4

335.173

130-01-8

5280906

White to off-white solid powder

1.3±0.1 g/cm3

563.7±50.0 °C at 760 mmHg

236ºC(lit.)

294.7±30.1 °C

0.0±3.5 mmHg at 25°C

1.570

0.88

1

6

0

24

611

4

C/C=C\1/C[C@H]([C@@](C(=O)OCC2=CCN3[C@H]2[C@@H](CC3)OC1=O)(C)O)C

HKODIGSRFALUTA-JTLQZVBZSA-N

InChI=1S/C18H25NO5/c1-4-12-9-11(2)18(3,22)17(21)23-10-13-5-7-19-8-6-14(15(13)19)24-16(12)20/h4-5,11,14-15,22H,6-10H2,1-3H3/b12-4-/t11-,14-,15-,18-/m1/s1

(1R,4Z,6R,7R,17R)-4-ethylidene-7-hydroxy-6,7-dimethyl-2,9-dioxa-14-azatricyclo[9.5.1.014,17]heptadec-11-ene-3,8-dione

NSC-89935; NSC 89935; Senecionine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~1.43 mg/mL (~4.26 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)