Senecionine

Senecionine at a Glance

Senecionine is the pyrrolizidine alkaloid the rest of the class is measured against. It is a macrocyclic diester of retronecine, named for Senecio — the ragworts and groundsels that poison livestock — and it occurs alongside its N-oxide in coltsfoot, butterbur and comfrey’s wider relatives.

Structurally it belongs to the most dangerous subtype of an unevenly dangerous class. Assayed side by side in the same genotoxicity test, sixteen pyrrolizidine alkaloids spanned roughly a thousandfold in potency, with macrocyclic diesters like senecionine at the top and the 7-hydroxy monoesters such as lycopsamine at the bottom ^{11Reference 11Frei H et al. · 1992AnimalStructure/activity relationships of the genotoxic potencies of sixteen pyrrolizidine alkaloids assayed for the induction of somatic mutation and recombination in wing cells of Drosophila melanogaster — animal modelView study →}. Grouping them all as “PAs” is regulatory convenience, not chemistry.

Its toxicology is unusually well resolved for a plant toxin. Human liver CYP3A4 converts senecionine into a reactive dehydropyrrolizidine that attacks proteins and DNA, and the same enzyme also makes the N-oxide ^{1Reference 1Miranda CL et al. · 1991In vitroRole of cytochrome P450IIIA4 in the metabolism of the pyrrolizidine alkaloid senecionine in human liver — in vitroView study →}. What that reactive metabolite kills first is not the hepatocyte that made it but the sinusoidal endothelial cell next door — which is precisely why pyrrolizidine poisoning presents as hepatic veno-occlusive disease, a blockage of the liver’s small blood vessels, rather than as ordinary hepatitis ^{2Reference 2Hessel-Pras S et al. · 2020AnimalThe pyrrolizidine alkaloid senecionine induces CYP-dependent destruction of sinusoidal endothelial cells and cholestasis in mice — mouse in vivoView study →}.

The mechanism is shared with the other 1,2-unsaturated pyrrolizidines, and it is set out here in full rather than repeated across senkirkine, lycopsamine and intermedine.

What Makes It the Dangerous Kind

Two structural features have to be present for a pyrrolizidine alkaloid to be a poison, and senecionine has both in their most potent arrangement.

The first is a 1,2-unsaturated necine base — a double bond in the bicyclic core. Without it there is no metabolic activation and no toxicity, which is why coltsfoot’s other alkaloid, tussilagine, is harmless while senecionine is not, despite both being pyrrolizidines.

The second is how the base is esterified. Macrocyclic diesters, in which two ester links close a ring across the molecule, are the most genotoxic; open diesters come next; monoesters are least. The comparison was done directly, dosing sixteen alkaloids orally in the Drosophila wing-spot assay: all but one were genotoxic, but potency ranged across about three orders of magnitude, macrocyclic diesters at the top, 7-hydroxy monoesters at the bottom, and the ranking agreed with rodent hepatotoxicity ^{11Reference 11Frei H et al. · 1992AnimalStructure/activity relationships of the genotoxic potencies of sixteen pyrrolizidine alkaloids assayed for the induction of somatic mutation and recombination in wing cells of Drosophila melanogaster — animal modelView study →}. Senecionine is a macrocyclic diester.

The N-oxide is not an escape. Plants store much of their senecionine as senecionine N-oxide, which is not itself reactive but is reduced back to the free alkaloid in the gut, so analyses that measure only free bases understate the real exposure ^{7,9Reference 7Aydın AA · 2013Simultaneous investigation of sesquiterpenes, pyrrolizidine alkaloids and N-oxides in Butterbur (Petasites hybridus) with an offline 2D-combination of HPLC-UV and LC-MMI-ToF-MS — analyticalView study →Reference 9Kisielius V et al. · 2020The invasive butterbur contaminates stream and seepage water in groundwater wells with toxic pyrrolizidine alkaloids — analyticalView study →}. This is why modern surveys quantify both forms.

Bioactivation: CYP3A4 Makes the Poison

Senecionine is not toxic as it arrives. It is made toxic by the liver.

Human liver microsomes convert it into two major products: dehydropyrrolizidine (DHP), the reactive pyrrole that does the damage, and senecionine N-oxide, which is a detoxification product. Both reactions are catalysed by the same enzyme. Mechanism-based inactivators of CYP3A4 (gestodene, triacetyloleandomycin) markedly inhibited both, an antibody against CYP3A4 abolished DHP formation entirely in a low-activity liver sample and cut it by 90% in a high-activity one, and the rate of DHP production correlated almost perfectly with nifedipine oxidation, the classical CYP3A4 marker reaction ^{1Reference 1Miranda CL et al. · 1991In vitroRole of cytochrome P450IIIA4 in the metabolism of the pyrrolizidine alkaloid senecionine in human liver — in vitroView study →}.

The variation between people is the striking part. Across the human liver samples tested there was a 30-fold difference in DHP formation and a 25-fold difference in N-oxidation between the poorest and the best metaboliser ^{1Reference 1Miranda CL et al. · 1991In vitroRole of cytochrome P450IIIA4 in the metabolism of the pyrrolizidine alkaloid senecionine in human liver — in vitroView study →}. Since CYP3A4 activity is itself modulated by dozens of drugs and foods, that variability is a plausible reason why identical pyrrolizidine exposures produce such different outcomes — though nobody has demonstrated this clinically.

Once formed, DHP is an electrophile with two binding partners: proteins, giving the pyrrole-protein adducts now used as a human exposure biomarker ^{14,15Reference 14Ruan J et al. · 2015ReviewBlood pyrrole-protein adducts — a biomarker of pyrrolizidine alkaloid-induced liver injury in humans — reviewView study →Reference 15Ma J et al. · 2021Clinical trialClinical application of pyrrole-hemoglobin adducts as a biomarker of pyrrolizidine alkaloid exposure in humans — in patientsView study →}, and DNA, giving the adducts that underlie the class’s carcinogenicity ^{10,17Reference 10National Toxicology Program · 2003AnimalToxicology and carcinogenesis studies of riddelliine (CAS NoView study →Reference 17Mei N et al. · 2010ReviewMetabolism, genotoxicity, and carcinogenicity of comfrey — reviewView study →}.

The Cell That Dies First

The most illuminating recent work explains why pyrrolizidine liver injury looks the way it does. Senecionine was given to mice at an acutely toxic dose and the liver watched by intravital two-photon microscopy. What appeared was necrosis of the liver sinusoidal endothelial cells in the pericentral zone, with sinusoidal marker proteins in the serum and platelet aggregation in the damaged regions ^{2Reference 2Hessel-Pras S et al. · 2020AnimalThe pyrrolizidine alkaloid senecionine induces CYP-dependent destruction of sinusoidal endothelial cells and cholestasis in mice — mouse in vivoView study →}.

The elegant part is the control experiment. Senecionine applied directly to freshly isolated sinusoidal endothelial cells was not cytotoxic even at 500 µM — but after pre-incubation with primary hepatocytes, which activate it, the resulting medium killed those same endothelial cells with an EC₅₀ around 22 µM. Mice lacking cytochrome-P450 reductase showed no liver injury at all ^{2Reference 2Hessel-Pras S et al. · 2020AnimalThe pyrrolizidine alkaloid senecionine induces CYP-dependent destruction of sinusoidal endothelial cells and cholestasis in mice — mouse in vivoView study →}. So the poison is manufactured in the hepatocyte and exported to the endothelium next door.

That is hepatic sinusoidal obstruction syndrome — historically veno-occlusive disease — in mechanistic form: destroy the lining of the small hepatic veins and the blood cannot leave the liver. The same study found delayed uptake and elimination of a fluorescent bile-salt analogue and disturbed expression of bile-salt transporters, adding cholestasis to the picture ^{2Reference 2Hessel-Pras S et al. · 2020AnimalThe pyrrolizidine alkaloid senecionine induces CYP-dependent destruction of sinusoidal endothelial cells and cholestasis in mice — mouse in vivoView study →}.

Inside the hepatocyte, senecionine kills by a mitochondrial route: loss of membrane potential, cytochrome-c release, mitochondrial JNK activation and caspase-3-mediated apoptosis, preceded by dramatic fragmentation of the mitochondria. Blocking that fission pharmacologically, or deleting the fission protein Drp1 from hepatocytes, protected mice from senecionine liver injury ^{3Reference 3Yang X et al. · 2017AnimalInhibition of Drp1 protects against senecionine-induced mitochondria-mediated apoptosis in primary hepatocytes and in mice — mouse in vivoView study →}.

A Pyrrolizidine in a Plant That Never Made It

One unusual route deserves stating, because it is a real hazard for anyone gathering wild plants. Elephant’s head lousewort (Pedicularis groenlandica) is a root hemiparasite, and it takes senecionine up directly from a Senecio host plant and carries it in its own tissue. The uptake was demonstrated for this species by name ^{18Reference 18Schneider MJ · 1990Uptake of host plant alkaloids by root parasitic Pedicularis speciesView study →}.

The plant does not have the biosynthetic machinery to make pyrrolizidine alkaloids — it is simply plumbed into something that does. A specimen growing on Senecio triangularis carries senecionine; one growing elsewhere does not; and the two are indistinguishable by eye. Alkaloid content in a wildcrafted plant can therefore be a property of its neighbours rather than of its species.

What It's Used For

Senecionine has no therapeutic pharmacology and no dose. Its literature is mechanism, exposure assessment and analytical chemistry.

Evidence by IndicationStrength of support · Beta

01HepatotoxicityPromising70%Mouse intravital imaging with genetic controls, primary human and mouse hepatocytes, human liver microsomes ^{1,2,3Reference 1Miranda CL et al. · 1991In vitroRole of cytochrome P450IIIA4 in the metabolism of the pyrrolizidine alkaloid senecionine in human liver — in vitroView study →Reference 2Hessel-Pras S et al. · 2020AnimalThe pyrrolizidine alkaloid senecionine induces CYP-dependent destruction of sinusoidal endothelial cells and cholestasis in mice — mouse in vivoView study →Reference 3Yang X et al. · 2017AnimalInhibition of Drp1 protects against senecionine-induced mitochondria-mediated apoptosis in primary hepatocytes and in mice — mouse in vivoView study →}

02Genotoxicity & Carcinogenic PotentialPromising46%Structure-activity ranking + class-level regulatory assessment; the rodent bioassay is for riddelliine, not senecionine ^{10,11,12Reference 10National Toxicology Program · 2003AnimalToxicology and carcinogenesis studies of riddelliine (CAS NoView study →Reference 11Frei H et al. · 1992AnimalStructure/activity relationships of the genotoxic potencies of sixteen pyrrolizidine alkaloids assayed for the induction of somatic mutation and recombination in wing cells of Drosophila melanogaster — animal modelView study →Reference 12Dusemund B et al. · 2018ReviewRisk assessment of pyrrolizidine alkaloids in food of plant and animal origin — reviewView study →}

03Human Exposure & ContaminationPromising48%Analytical surveys of herbs, extracts and water; pyrrole-protein adduct biomarkers in patients ^{8,9,14,15Reference 8Schenk A et al. · 2015UPLC TOF MS for sensitive quantification of naturally occurring pyrrolizidine alkaloids in Petasites hybridus extract (Ze 339) — analyticalView study →Reference 9Kisielius V et al. · 2020The invasive butterbur contaminates stream and seepage water in groundwater wells with toxic pyrrolizidine alkaloids — analyticalView study →Reference 14Ruan J et al. · 2015ReviewBlood pyrrole-protein adducts — a biomarker of pyrrolizidine alkaloid-induced liver injury in humans — reviewView study →Reference 15Ma J et al. · 2021Clinical trialClinical application of pyrrole-hemoglobin adducts as a biomarker of pyrrolizidine alkaloid exposure in humans — in patientsView study →}

04Therapeutic UseShaky0%None proposed

Mechanisms

One fact organises the table: the liver builds the poison, and the neighbouring blood vessel absorbs it.

Pharmacokinetics

Senecionine’s disposition is dominated by first-pass metabolism, and the balance between its two CYP3A4 routes decides the outcome: DHP formation is bioactivation, N-oxidation is detoxification, and both rates vary 25–30-fold between human livers ^{1Reference 1Miranda CL et al. · 1991In vitroRole of cytochrome P450IIIA4 in the metabolism of the pyrrolizidine alkaloid senecionine in human liver — in vitroView study →}. The N-oxide is not a terminal metabolite in practice, because gut microbiota reduce it back to the parent alkaloid, which is why an N-oxide-rich plant is not a safer plant ^{9,12Reference 9Kisielius V et al. · 2020The invasive butterbur contaminates stream and seepage water in groundwater wells with toxic pyrrolizidine alkaloids — analyticalView study →Reference 12Dusemund B et al. · 2018ReviewRisk assessment of pyrrolizidine alkaloids in food of plant and animal origin — reviewView study →}. Glucuronidation provides a further clearance route. The reactive metabolite is short-lived but its adducts are not — pyrrole-protein and pyrrole-haemoglobin adducts persist long enough to serve as exposure biomarkers in patients ^{14,15Reference 14Ruan J et al. · 2015ReviewBlood pyrrole-protein adducts — a biomarker of pyrrolizidine alkaloid-induced liver injury in humans — reviewView study →Reference 15Ma J et al. · 2021Clinical trialClinical application of pyrrole-hemoglobin adducts as a biomarker of pyrrolizidine alkaloid exposure in humans — in patientsView study →}. No human pharmacokinetic study exists, and none should be expected.

Clinical Trials

None, and none is possible. The human evidence consists of poisoning case series across the pyrrolizidine class, biomarker studies in exposed patients ^{14,15Reference 14Ruan J et al. · 2015ReviewBlood pyrrole-protein adducts — a biomarker of pyrrolizidine alkaloid-induced liver injury in humans — reviewView study →Reference 15Ma J et al. · 2021Clinical trialClinical application of pyrrole-hemoglobin adducts as a biomarker of pyrrolizidine alkaloid exposure in humans — in patientsView study →}, and analytical exposure surveys ^{8,9,12Reference 8Schenk A et al. · 2015UPLC TOF MS for sensitive quantification of naturally occurring pyrrolizidine alkaloids in Petasites hybridus extract (Ze 339) — analyticalView study →Reference 9Kisielius V et al. · 2020The invasive butterbur contaminates stream and seepage water in groundwater wells with toxic pyrrolizidine alkaloids — analyticalView study →Reference 12Dusemund B et al. · 2018ReviewRisk assessment of pyrrolizidine alkaloids in food of plant and animal origin — reviewView study →}.

Last checked: September 2026.

Isolate vs. Plant Studies

Unusually for a plant constituent, the isolate work is the relevant work: purified senecionine in human liver microsomes ^{1Reference 1Miranda CL et al. · 1991In vitroRole of cytochrome P450IIIA4 in the metabolism of the pyrrolizidine alkaloid senecionine in human liver — in vitroView study →}, in primary hepatocytes and mice ^{2,3Reference 2Hessel-Pras S et al. · 2020AnimalThe pyrrolizidine alkaloid senecionine induces CYP-dependent destruction of sinusoidal endothelial cells and cholestasis in mice — mouse in vivoView study →Reference 3Yang X et al. · 2017AnimalInhibition of Drp1 protects against senecionine-induced mitochondria-mediated apoptosis in primary hepatocytes and in mice — mouse in vivoView study →}, and in HepaRG cells ^{4Reference 4Waizenegger J et al. · 2018In vitroStructure-dependent induction of apoptosis by hepatotoxic pyrrolizidine alkaloids in the human hepatoma cell line HepaRG: Single versus repeated exposure — in vitroView study →}. There is no argument here about whether the whole plant behaves differently in some beneficial way — the alkaloid is the hazard, and the question a herb page has to answer is simply how much of it is present.

Where plant context does matter is in mixtures and N-oxides. Plants deliver senecionine alongside seneciphylline, senkirkine and the N-oxides of each ^{7,8,9Reference 7Aydın AA · 2013Simultaneous investigation of sesquiterpenes, pyrrolizidine alkaloids and N-oxides in Butterbur (Petasites hybridus) with an offline 2D-combination of HPLC-UV and LC-MMI-ToF-MS — analyticalView study →Reference 8Schenk A et al. · 2015UPLC TOF MS for sensitive quantification of naturally occurring pyrrolizidine alkaloids in Petasites hybridus extract (Ze 339) — analyticalView study →Reference 9Kisielius V et al. · 2020The invasive butterbur contaminates stream and seepage water in groundwater wells with toxic pyrrolizidine alkaloids — analyticalView study →}, and work on comfrey’s monoester alkaloids found a crude alkaloid extract more toxic than the purified alkaloids given at the same dose, implying interaction between them. Exposure limits derived from single compounds may therefore understate what a plant delivers, which is part of why regulators assess the alkaloids as a group ^{12Reference 12Dusemund B et al. · 2018ReviewRisk assessment of pyrrolizidine alkaloids in food of plant and animal origin — reviewView study →}.

Its Role in Plants

Pyrrolizidine alkaloids are chemical defence against herbivores, and their biosynthesis is one of the better-understood specialised pathways in plants: it begins with homospermidine synthase, an enzyme recruited from the housekeeping enzyme deoxyhypusine synthase, which is why the pathway has arisen independently in several unrelated families ^{16Reference 16Schramm S et al. · 2019ReviewPyrrolizidine alkaloids: biosynthesis, biological activities and occurrence in crop plants — reviewView study →}. In Senecio the alkaloids are made in the roots and transported as N-oxides to the shoots, where they are stored.

Some insects have turned the defence around: arctiid moths and other specialists sequester senecionine from their food plants, store it, and use it for their own protection and as a precursor to pheromones. The alkaloid that poisons a cow is a resource to a moth.

Prevalence in Nature

Senecionine is a hallmark alkaloid of the tribe Senecioneae in the Asteraceae. Its namesake genus Senecio — ragworts and groundsels — is the classic source and the cause of most livestock pyrrolizidine poisoning worldwide.

Among herbs, it is detected analytically in coltsfoot (Tussilago farfara) together with senkirkine ^{6Reference 6Cao K et al. · 2016Sensitive determination of pyrrolizidine alkaloids in Tussilago farfara L. by field-amplified, sample-stacking, sweeping micellar electrokinetic chromatography — analyticalView study →}, and in butterbur (Petasites hybridus) rhizome with its N-oxide alongside senkirkine and seneciphylline ^{7,8Reference 7Aydın AA · 2013Simultaneous investigation of sesquiterpenes, pyrrolizidine alkaloids and N-oxides in Butterbur (Petasites hybridus) with an offline 2D-combination of HPLC-UV and LC-MMI-ToF-MS — analyticalView study →Reference 8Schenk A et al. · 2015UPLC TOF MS for sensitive quantification of naturally occurring pyrrolizidine alkaloids in Petasites hybridus extract (Ze 339) — analyticalView study →}. Field measurements beside invasive butterbur stands found senkirkine, senecionine and senecionine N-oxide as the dominant alkaloids in both the plants and the surrounding water ^{9Reference 9Kisielius V et al. · 2020The invasive butterbur contaminates stream and seepage water in groundwater wells with toxic pyrrolizidine alkaloids — analyticalView study →}.

Two routes carry it outside the plants that make it. The first is the food chain: pyrrolizidine alkaloids appear in honey from PA-bearing forage, in milk, and as crop contaminants, with herbal teas the main dietary source in European assessment ^{12Reference 12Dusemund B et al. · 2018ReviewRisk assessment of pyrrolizidine alkaloids in food of plant and animal origin — reviewView study →}. The second is root hemiparasitism — elephant’s head lousewort takes senecionine directly from a Senecio host ^{18Reference 18Schneider MJ · 1990Uptake of host plant alkaloids by root parasitic Pedicularis speciesView study →}.

Discovery & Synthesis

Senecionine was characterised from Senecio early in the twentieth century, part of the chemical investigation of the livestock poisonings that made ragwort a notifiable weed in several countries, and it takes its name from the genus. It became the reference compound of pyrrolizidine toxicology: the 1991 demonstration that human CYP3A4 performs both its activation and its detoxification was done on senecionine ^{1Reference 1Miranda CL et al. · 1991In vitroRole of cytochrome P450IIIA4 in the metabolism of the pyrrolizidine alkaloid senecionine in human liver — in vitroView study →}, and it is one of the standard alkaloids in structure-activity comparisons ^{4,11Reference 4Waizenegger J et al. · 2018In vitroStructure-dependent induction of apoptosis by hepatotoxic pyrrolizidine alkaloids in the human hepatoma cell line HepaRG: Single versus repeated exposure — in vitroView study →Reference 11Frei H et al. · 1992AnimalStructure/activity relationships of the genotoxic potencies of sixteen pyrrolizidine alkaloids assayed for the induction of somatic mutation and recombination in wing cells of Drosophila melanogaster — animal modelView study →}.

It is not manufactured. Senecionine is isolated from plant material for use as an analytical standard and a research toxin, and the commercial interest runs entirely the other way — toward reference standards accurate enough to detect it at parts per billion in food, herbal extracts and water ^{8,9Reference 8Schenk A et al. · 2015UPLC TOF MS for sensitive quantification of naturally occurring pyrrolizidine alkaloids in Petasites hybridus extract (Ze 339) — analyticalView study →Reference 9Kisielius V et al. · 2020The invasive butterbur contaminates stream and seepage water in groundwater wells with toxic pyrrolizidine alkaloids — analyticalView study →}.

Toxicity & Safety

Senecionine is flagged toxic and carcinogen, and both are literal. It is a hepatotoxin with a mapped mechanism and a member of a class assessed as genotoxic carcinogens with no threshold.

The Injury It Causes

Pyrrolizidine liver injury is hepatic sinusoidal obstruction syndrome — the small hepatic veins are blocked by damage to their endothelial lining, and blood cannot drain from the liver. It presents with abdominal pain, ascites, hepatomegaly and jaundice, and it can be fatal or leave permanent damage. The mechanism is set out above: hepatocytes make the reactive metabolite and the neighbouring endothelial cells die of it ^{2Reference 2Hessel-Pras S et al. · 2020AnimalThe pyrrolizidine alkaloid senecionine induces CYP-dependent destruction of sinusoidal endothelial cells and cholestasis in mice — mouse in vivoView study →}. Cholestasis accompanies it ^{2Reference 2Hessel-Pras S et al. · 2020AnimalThe pyrrolizidine alkaloid senecionine induces CYP-dependent destruction of sinusoidal endothelial cells and cholestasis in mice — mouse in vivoView study →}. There is no antidote.

Exposure Limits

There is no safe intake. The European chronic assessment for 1,2-unsaturated pyrrolizidine alkaloids works from a BMDL₁₀ of 237 µg/kg body weight per day derived from riddelliine data, and names herbal teas and teas as the main dietary source ^{12Reference 12Dusemund B et al. · 2018ReviewRisk assessment of pyrrolizidine alkaloids in food of plant and animal origin — reviewView study →}; a proposed acute reference dose of 1 µg/kg body weight per day was later derived from a sub-acute rat study and supported by human poisoning cases ^{13Reference 13Eckert E et al. · 2023ReviewRisk assessment of short-term intake of pyrrolizidine alkaloids in food: derivation of an acute reference dose — reviewView study →}. Regulatory limits for herbal medicines now sit at levels requiring parts-per-billion analytical methods ^{8Reference 8Schenk A et al. · 2015UPLC TOF MS for sensitive quantification of naturally occurring pyrrolizidine alkaloids in Petasites hybridus extract (Ze 339) — analyticalView study →}.

Who Is At Risk

Anyone consuming a pyrrolizidine-bearing plant internally, in any preparation — hot water does not exclude these alkaloids, and neither does alcohol. Because bioactivation runs through CYP3A4, and that enzyme’s activity varies 30-fold between people and is modulated by many drugs, exposure and susceptibility are both variable ^{1Reference 1Miranda CL et al. · 1991In vitroRole of cytochrome P450IIIA4 in the metabolism of the pyrrolizidine alkaloid senecionine in human liver — in vitroView study →}; this is mechanistically obvious and clinically unstudied. Children, pregnant women (the alkaloids cross the placenta as a class) and people with existing liver disease are the conventional high-risk groups. Plants containing senecionine should not be taken internally, and the decision about any particular herb belongs on that herb’s page, where preparation and alkaloid content are known.

Safety at a Glance

☠️ ToxicLiver risk

• Hepatotoxic with no safe intake. CYP3A4 converts it to a reactive pyrrole that destroys the lining of the liver’s small veins, causing sinusoidal obstruction syndrome.
• Genotoxic carcinogen by class. Its close relative riddelliine caused liver haemangiosarcomas in most treated rats at 1 mg/kg.
• The N-oxide is not a safe form. Gut bacteria reduce it back to the alkaloid, so analyses that ignore N-oxides understate exposure.
• Susceptibility varies 30-fold. Bioactivation depends on CYP3A4 activity, which differs widely between people and is altered by many drugs.
• Exposure reaches beyond herbs. Honey, milk, contaminated crops, and stream and well water near butterbur stands.
• Depleted extracts are a different product. The commercial butterbur extract Ze 339 had no detectable pyrrolizidine alkaloids down to 2 ppb.

Dosage

There is no dose, and no preparation should be taken to obtain senecionine. The relevant numbers are limits and measured contamination.

References

1. Miranda CL, Reed RL, Guengerich FP, et al. (1991). Role of cytochrome P450IIIA4 in the metabolism of the pyrrolizidine alkaloid senecionine in human liver — in vitro. Carcinogenesis. https://pubmed.ncbi.nlm.nih.gov/2009596/
2. Hessel-Pras S, Braeuning A, Guenther G, et al. (2020). The pyrrolizidine alkaloid senecionine induces CYP-dependent destruction of sinusoidal endothelial cells and cholestasis in mice — mouse in vivo. Arch Toxicol. https://pubmed.ncbi.nlm.nih.gov/31606820/
3. Yang X, Wang H, Ni HM, et al. (2017). Inhibition of Drp1 protects against senecionine-induced mitochondria-mediated apoptosis in primary hepatocytes and in mice — mouse in vivo. Redox Biol. https://pubmed.ncbi.nlm.nih.gov/28282614/
4. Waizenegger J, Braeuning A, Templin M, et al. (2018). Structure-dependent induction of apoptosis by hepatotoxic pyrrolizidine alkaloids in the human hepatoma cell line HepaRG: Single versus repeated exposure — in vitro. Food Chem Toxicol. https://pubmed.ncbi.nlm.nih.gov/29458164/
5. Hirono I, Mori H, Culvenor CC (1976). Carcinogenic activity of coltsfoot, Tussilago farfara L. — rat in vivo. Gan. https://pubmed.ncbi.nlm.nih.gov/1269853/
6. Cao K, Xu Y, Mu X, et al. (2016). Sensitive determination of pyrrolizidine alkaloids in Tussilago farfara L. by field-amplified, sample-stacking, sweeping micellar electrokinetic chromatography — analytical. J Sep Sci. https://pubmed.ncbi.nlm.nih.gov/27673325/
7. Aydın AA, Letzel T (2013). Simultaneous investigation of sesquiterpenes, pyrrolizidine alkaloids and N-oxides in Butterbur (Petasites hybridus) with an offline 2D-combination of HPLC-UV and LC-MMI-ToF-MS — analytical. J Pharm Biomed Anal. https://pubmed.ncbi.nlm.nih.gov/23906985/
8. Schenk A, Siewert B, Toff S, et al. (2015). UPLC TOF MS for sensitive quantification of naturally occurring pyrrolizidine alkaloids in Petasites hybridus extract (Ze 339) — analytical. J Chromatogr B Analyt Technol Biomed Life Sci. https://pubmed.ncbi.nlm.nih.gov/26094206/
9. Kisielius V, Hama JR, Skrbic N, et al. (2020). The invasive butterbur contaminates stream and seepage water in groundwater wells with toxic pyrrolizidine alkaloids — analytical. Sci Rep. https://pubmed.ncbi.nlm.nih.gov/33188248/
10. National Toxicology Program (2003). Toxicology and carcinogenesis studies of riddelliine (CAS No. 23246-96-0) in F344/N rats and B6C3F1 mice (gavage studies) — animal in vivo. Natl Toxicol Program Tech Rep Ser. https://pubmed.ncbi.nlm.nih.gov/12844193/
11. Frei H, Lüthy J, Brauchli J, et al. (1992). Structure/activity relationships of the genotoxic potencies of sixteen pyrrolizidine alkaloids assayed for the induction of somatic mutation and recombination in wing cells of Drosophila melanogaster — animal model. Chem Biol Interact. https://pubmed.ncbi.nlm.nih.gov/1643665/
12. Dusemund B, Nowak N, Sommerfeld C, et al. (2018). Risk assessment of pyrrolizidine alkaloids in food of plant and animal origin — review. Food Chem Toxicol. https://pubmed.ncbi.nlm.nih.gov/29524571/
13. Eckert E, Lepper H, Hintzsche H (2023). Risk assessment of short-term intake of pyrrolizidine alkaloids in food: derivation of an acute reference dose — review. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. https://pubmed.ncbi.nlm.nih.gov/36794362/
14. Ruan J, Gao H, Li N, et al. (2015). Blood pyrrole-protein adducts — a biomarker of pyrrolizidine alkaloid-induced liver injury in humans — review. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. https://pubmed.ncbi.nlm.nih.gov/26398275/
15. Ma J, Zhang W, He Y, et al. (2021). Clinical application of pyrrole-hemoglobin adducts as a biomarker of pyrrolizidine alkaloid exposure in humans — in patients. Arch Toxicol. https://pubmed.ncbi.nlm.nih.gov/33210216/
16. Schramm S, Köhler N, Rozhon W (2019). Pyrrolizidine alkaloids: biosynthesis, biological activities and occurrence in crop plants — review. Molecules. https://pubmed.ncbi.nlm.nih.gov/30704105/
17. Mei N, Guo L, Fu PP, et al. (2010). Metabolism, genotoxicity, and carcinogenicity of comfrey — review. J Toxicol Environ Health B Crit Rev. https://pubmed.ncbi.nlm.nih.gov/21170807/
18. Schneider MJ, Stermitz FR (1990). Uptake of host plant alkaloids by root parasitic Pedicularis species. Phytochemistry. https://doi.org/10.1016/0031-9422(90)85021-7

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