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
Animal studies showed that the highest concentrations were found in the liver, lungs, kidneys, and spleen. /Pyrrolizidine Alkaloids/
The concentration of pyrrolizidine alkaloids in the blood of rats after intraperitoneal injection of 0.1 LD50 was determined. At 0.5, 1, and 2 hours post-injection, the blood concentrations of pyrrolizidine alkaloids were 0.38, 0.32, and 0.14 mg/L, respectively.
…The distribution, excretion, transfer to milk, and covalent binding of pyrrolizidine alkaloids to liver macromolecules in BALB/c mice were investigated. Following injection, the radioactive material was rapidly excreted (84% or more) in urine and feces within 16 hours. After 16 hours, the liver contained more than 1.5% of the dose. Within 16 hours, a small amount (0.04%) of the dose was transferred to milk; most of the radioactive material was present in the skim milk fraction, indicating that PA was transferred to milk as a water-soluble metabolite. …The binding of pyrrolizidine alkaloids to calf thymus DNA and microsomal macromolecules was determined in vitro. Binding was reduced in the absence of oxygen or NADPH-generating systems, or by boiling microsomes. … Bile, urine, and blood samples were collected within 7 hours after intravenous injection of [14C]SEN (60 mg/kg, 10 μCi/kg). Of the total administered radioactive material, 44% and 43% were excreted in bile and urine, respectively. Mass spectrometry analysis identified Senox as the major metabolite in bile (52% of 44%) and urine (30% of 43%). Less than 5% of the parent alkaloid was excreted in bile and less than 18% in urine over the total 7 hours.

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Metabolism/Metabolites
The metabolism of pyrrolizidine alkaloids in male rat liver microsomes pretreated with phenobarbital was tested to be N-oxide and pyrrole.
The in vitro mouse liver microsomal metabolism of the macrocyclic pyrrolizidine alkaloid Senox was investigated. Sesquidonic acid, sesquidine N-oxide, and a novel metabolite, 19-hydroxysesquidine, were isolated from the microsomal enzyme system of balb/c mice. Toxic pyrrolizidine alkaloids, such as sesquidine, are cyclic aromatic amines that are dehydrogenated by cytochrome P450 (CYP3A4) to produce the corresponding pyrroles. Pyrrole itself is a nucleophile, but the removal of substituents from the pyrrolidine ring generates an electrophile… In animals, the main metabolic pathways for pyrrolidine alkaloids are: (a) ester hydrolysis; (b) N-oxidation; and (c) dehydrogenation of the pyrrolidine ring to produce pyrrole derivatives. Pathways (a) and (b) are considered detoxification mechanisms. Pathway (c) produces toxic metabolites. Pathway (a) occurs in the liver and blood; pathways (b) and (c) are catalyzed by the hepatic microsomal mixed-function oxidase system. /Pyrrolizidine Alkaloids/
For more complete metabolite/metabolite data on senna alkaloids (7 metabolites in total), please visit the HSDB record page.

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Biological Half-Life
Only a relatively small percentage of the administered dose remains in the body within a few hours. The majority remains as metabolites bound to tissue components. Following intravenous injection in animals, pyrrolizidine N-oxide disappears from serum with an initial half-life of 3 to 20 minutes. /Pyrrolizidine Alkaloids/

Toxicity Summary
Sesquidine belongs to the pyrrolizidine alkaloid family (PA). Unsaturated pyrrolizidine alkaloids are hepatotoxic, meaning they damage the liver. Pyrrolizidine alkaloids can also cause hepatic veno-occlusive disease and liver cancer. Pyrrolizidine alkaloids are tumorigenic. Diseases associated with the ingestion of pyrrolizidine alkaloids are called pyrrolizidine alkaloid poisoning. (Wikipedia) Studies have shown that the pyrrolizidine alkaloid sesquidine can lead to an increase in the concentration of free Ca2+ in the cytoplasm of isolated hepatocytes, and this increase is associated with increased cytotoxicity. Cytotoxicity is higher in the absence of extracellular Ca2+ than in the presence of extracellular Ca2+, suggesting that altered intracellular Ca2+ distribution, rather than the influx of extracellular Ca2+, is the cause of sesquidine-induced hepatotoxicity. Studies have shown that sesquidine has hepatotoxicity, genotoxicity, and cytotoxicity. In isolated rat hepatocytes, sesquidine can induce membrane lipid peroxidation in a dose-dependent manner. Alterations in intracellular Ca2+ concentration are also considered one of the main possible mechanisms of cytotoxicity. (A15422) Numerous studies have shown that senna-induced hepatotoxicity is associated with lipid peroxidation, alterations in intracellular Ca2+ concentration, and depletion of intracellular glutathione. (A15423)

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Interactions
We purified three P450 enzymes from phenobarbital (PB)-treated guinea pig liver to evaluate their roles in the metabolism of pyrrolizidine alkaloids (PA). PB treatment of guinea pigs increased the conversion of PA senna (SN) in liver microsomes to the pyrrole metabolites (+/-)6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolazine (DHP, an activated product) and SN N-oxide (a detoxification product) by 224% and 70%, respectively. ...The second purified guinea pig P450, a type 2C isoenzyme (M(r) = 56,496 as determined by MALDI-TOF mass spectrometry), generated SN N-oxide from SN at a rate of 13.3 min⁻¹, but catalyzed very little DHP production. The third guinea pig P450 enzyme, phenotype 3A (molecular weight 54,000-56,000 as determined by SDS-PAGE), lost its SN catalytic activity during final purification.

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Non-human toxicity values
Hamster intravenous LD50: 611 mg/kg
Rat intravenous LD50: 41.2 mg/kg
Mouse intravenous LD50: 64 mg/kg
Rat intraperitoneal LD50: 50 mg/kg /Data 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 plants of the genus Senecio. It is a plant metabolite. It is a lactone, a pyrrolizidine alkaloid, and a tertiary alcohol. Its function is related to senecionan. It is the conjugate base of Senecionine (1+). Senecionine has been reported in Jacobaea carniolica, Senecio rodriguezii, and other organisms with relevant data. Senecionine is an organic compound with the chemical formula C18H25NO5. It is classified as a pyrrolizidine alkaloid. See also: Petasites hybridus root (part); Tussilago farfara flower (part); Tussilago farfara leaf (part).

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Mechanism of Action
In isolated guinea pig ileum specimens, broadleaf alkaloids, thapirine, hellerialine, and cypermethrin exhibited stronger antagonistic effects against acetylcholine (ii). Their anticholinergic activity appears to involve a competitive mechanism. Pyrrolizidine alkaloids showed little antagonistic effect against acetylcholine in isolated toad rectus abdominis muscle specimens (ii).
Mixed-function oxidases activate alkaloids to produce pyrrole dehydroalkaloids, which are active alkylating agents. Metabolites bind to hepatocytes, leading to liver necrosis. Some metabolites are released into the bloodstream and are believed to reach the lungs via the liver, causing vascular damage. Pyrrole metabolites are cytotoxic, acting on hepatocytes as well as vascular endothelial cells in the liver and lungs. /Pyrrolizidine Alkaloids/
Senecio scabra alkaloids show antispasmodic activity, primarily acting on intestinal smooth muscle.

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Therapeutic Uses
Senecio scabra is used in folk remedies for diabetes, bleeding, hypertension, and spasms, and as a uterine stimulant.

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Drug Warning
Senecio scandens contains varying amounts of toxic pyrrolizidine alkaloids (PA), which are known to have organ toxicity, especially hepatotoxicity.
Due to insufficient or lack of supporting evidence for its therapeutic efficacy and the presence of toxic pyrrolizidine alkaloids, Senecio scandens should not be used for treatment.

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.)