Senkirkine

Senkirkine at a Glance

Senkirkine is the pyrrolizidine alkaloid that gave coltsfoot its reputation as a liver carcinogen. When pre-blooming coltsfoot flowers were fed to rats for 600 days, 8 of 12 animals in the highest-dose group developed haemangioendothelial sarcoma of the liver, and the chemical analysis of the material pointed at senkirkine as the responsible compound ^{1Reference 1Hirono I et al. · 1976AnimalCarcinogenic activity of coltsfoot, Tussilago farfara L. — rat in vivoView study →}.

Chemically it is the odd one out of its class. Most toxic pyrrolizidines — senecionine, lycopsamine, intermedine — are retronecine-type, with a bridgehead nitrogen that plants routinely store as an N-oxide. Senkirkine is otonecine-type: the ring is opened and the nitrogen carries a methyl group, so it does not travel with an N-oxide partner the way the others do, and analytical panels for butterbur quantify senecionine and seneciphylline with their N-oxides but senkirkine alone ^{4Reference 4Aydın 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 →}.

That structural difference shows up in cells as a difference in speed rather than in kind. In human liver cells, retronecine-type alkaloids were cytotoxic and pro-apoptotic after a single 24-hour exposure while senkirkine was not — but after 14 days of repeated dosing all of them were, senkirkine included ^{3Reference 3Waizenegger 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 →}. And in rats, senkirkine produces exactly the same four DNA adducts as the other tumorigenic pyrrolizidines ^{7Reference 7Xia Q et al. · 2013AnimalPyrrolizidine alkaloid-derived DNA adducts as a common biological biomarker of pyrrolizidine alkaloid-induced tumorigenicity — rat in vivoView study →}. It reaches the same place by a slower road.

The hepatic mechanism it shares with the rest of the class — bioactivation to a reactive pyrrole, destruction of the liver’s sinusoidal endothelial cells, veno-occlusive disease — is set out in full on the senecionine page rather than repeated here.

An Otonecine-Type Alkaloid

Pyrrolizidine alkaloids divide by their necine base, the bicyclic core they are built on, and the division is not cosmetic.

Retronecine-type alkaloids have an intact bicyclic amine with a bridgehead nitrogen. That nitrogen is readily oxidised, so plants store large fractions of these alkaloids as N-oxides — which are not themselves reactive but are reduced back to the parent alkaloid by gut bacteria, making them a delayed rather than a defused form.

Otonecine-type alkaloids like senkirkine have a ring-opened, N-methylated eight-membered necine base with a ketone. The nitrogen is a tertiary amine bearing a methyl group and does not give the same N-oxide chemistry, which is why butterbur analytical methods list senecionine N-oxide and seneciphylline N-oxide but no senkirkine N-oxide ^{4Reference 4Aydın 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 →}. To become the reactive pyrrole, an otonecine-type alkaloid must first undergo oxidative N-demethylation — an extra metabolic step the retronecine-type alkaloids do not need.

That extra step is the most plausible explanation for the timing difference in cells. Tested in human HepaRG hepatoma cells, retronecine-type alkaloids (echimidine, senecionine) and the heliotridine-type heliotrine behaved differently from senkirkine: after 24 hours only the retronecine-type alkaloids were cytotoxic, disrupting mitochondrial membrane potential and cleaving caspases, whereas after 14 days of repeated exposure all four alkaloids produced those effects, and the authors concluded retronecine-type alkaloids are the more potent apoptosis inducers ^{3Reference 3Waizenegger 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 →}. Senkirkine is slower, not safe — and repeated low-level exposure is exactly the pattern that herbal use produces.

The Coltsfoot Result

Coltsfoot is one of the few herbs whose carcinogenicity was tested directly, and the result is the reason senkirkine has a reputation at all.

Inbred ACI rats were fed diets containing pre-blooming coltsfoot flowers for 600 days. The high-dose group received 32% coltsfoot for four days and 16% thereafter; 8 of 12 rats developed hepatic haemangioendothelial sarcoma. At 8% coltsfoot, 1 of 10 rats developed the tumour. At 4%, none did. Chemical analysis of the flowers used led the authors to conclude that the carcinogenicity was “most probably due to senkirkine” ^{1Reference 1Hirono I et al. · 1976AnimalCarcinogenic activity of coltsfoot, Tussilago farfara L. — rat in vivoView study →}.

Three qualifications belong with that study. The dose was enormous — 16% of the diet is not a herbal exposure, and the dose-response fell away sharply, to a single tumour at 8% and none at 4%. The material was flower buds, the part richest in alkaloids. And the attribution to senkirkine was inferential, from the chemistry of the material rather than from dosing the pure alkaloid.

What the study nonetheless established is that a coltsfoot preparation can be carcinogenic in a mammal, on the same target organ and the same tumour type that pyrrolizidine alkaloids produce elsewhere. Modern analysis confirms senkirkine and senecionine are both present in Tussilago farfara, with senkirkine detectable even in a simple acid extract ^{2Reference 2Cao K et al. · 2016Sensitive determination of pyrrolizidine alkaloids in Tussilago farfara L. by field-amplified, sample-stacking, sweeping micellar electrokinetic chromatography — analyticalView study →}. Coltsfoot’s traditional use as a cough herb now sits under that finding, and PA-free cultivars have been developed in response.

What It's Used For

Senkirkine has no therapeutic pharmacology. Its literature is genotoxicity, the coltsfoot bioassay, and analytical chemistry.

Evidence by IndicationStrength of support · Beta

01CarcinogenicityPromising56%600-day rat feeding study of coltsfoot + DNA-adduct formation in rats gavaged with senkirkine itself ^{1,7Reference 1Hirono I et al. · 1976AnimalCarcinogenic activity of coltsfoot, Tussilago farfara L. — rat in vivoView study →Reference 7Xia Q et al. · 2013AnimalPyrrolizidine alkaloid-derived DNA adducts as a common biological biomarker of pyrrolizidine alkaloid-induced tumorigenicity — rat in vivoView study →}

02GenotoxicityPromising48%Ames TA100 with S9 pre-incubation; the DHP-adduct series; class structure-activity ranking ^{6,7,8Reference 6Yamanaka H et al. · 1979In vitroMutagenicity of pyrrolizidine alkaloids in the Salmonella/mammalian-microsome test — in vitroView study →Reference 7Xia Q et al. · 2013AnimalPyrrolizidine alkaloid-derived DNA adducts as a common biological biomarker of pyrrolizidine alkaloid-induced tumorigenicity — rat in vivoView study →Reference 8Frei 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 →}

03HepatotoxicityShaky40%Human HepaRG cells, repeated-exposure design; the class mechanism established for senecionine ^{3Reference 3Waizenegger 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 →}

04Human Exposure & ContaminationShaky42%Coltsfoot and butterbur analyses, PA-free extract quantification, environmental water survey ^{2,4,5Reference 2Cao K et al. · 2016Sensitive determination of pyrrolizidine alkaloids in Tussilago farfara L. by field-amplified, sample-stacking, sweeping micellar electrokinetic chromatography — analyticalView study →Reference 4Aydın 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 5Schenk A et al. · 2015UPLC TOF MS for sensitive quantification of naturally occurring pyrrolizidine alkaloids in Petasites hybridus extract (Ze 339) — analyticalView study →}

05Therapeutic UseShaky0%None proposed

Mechanisms

The otonecine ring buys time, not safety: the same adducts, the same tumour type, on a slower schedule.

Pharmacokinetics

No dedicated pharmacokinetic study of senkirkine was found, and its disposition is inferred from its structural class. Two differences from the retronecine-type alkaloids are worth stating. First, it does not carry the N-oxide problem — the plant does not store it as an N-oxide requiring gut reduction, so the free alkaloid is what is ingested. Second, activation requires oxidative N-demethylation before the reactive pyrrole can form, an extra step that is the likeliest reason for the slower cell-level toxicity ^{3Reference 3Waizenegger 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 →}. Downstream, its reactive metabolite behaves exactly like the others, forming the same DHP-DNA adducts in rat liver ^{7Reference 7Xia Q et al. · 2013AnimalPyrrolizidine alkaloid-derived DNA adducts as a common biological biomarker of pyrrolizidine alkaloid-induced tumorigenicity — rat in vivoView study →}. Human data do not exist and will not be generated.

Clinical Trials

None, and none is possible. The human evidence is class-level poisoning literature and analytical exposure assessment ^{5,9Reference 5Schenk 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 →}.

Last checked: September 2026.

Isolate vs. Plant Studies

The evidence splits neatly and unusually. The carcinogenicity result is a plant study — whole coltsfoot flowers in the diet, with senkirkine named by inference from the chemistry ^{1Reference 1Hirono I et al. · 1976AnimalCarcinogenic activity of coltsfoot, Tussilago farfara L. — rat in vivoView study →}. The mechanistic and genotoxicity results are isolate studies — purified senkirkine in the Ames test ^{6Reference 6Yamanaka H et al. · 1979In vitroMutagenicity of pyrrolizidine alkaloids in the Salmonella/mammalian-microsome test — in vitroView study →}, gavaged into rats for adduct analysis ^{7Reference 7Xia Q et al. · 2013AnimalPyrrolizidine alkaloid-derived DNA adducts as a common biological biomarker of pyrrolizidine alkaloid-induced tumorigenicity — rat in vivoView study →}, and dosed to human liver cells beside its structural relatives ^{3Reference 3Waizenegger 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 →}.

Neither side can be substituted for the other. The coltsfoot bioassay cannot prove senkirkine caused the tumours, since the flowers also contained senecionine; the adduct and mutagenicity work proves senkirkine does the chemistry a liver carcinogen does, without producing a tumour incidence for it. Together they make a coherent case, and they are why coltsfoot’s status changed.

Prevalence in Nature

Senkirkine is an alkaloid of the tribe Senecioneae in the Asteraceae. Its best-known source is coltsfoot (Tussilago farfara), where it is the principal pyrrolizidine alkaloid, concentrated in the flower buds and detectable alongside senecionine in leaf material ^{1,2Reference 1Hirono I et al. · 1976AnimalCarcinogenic activity of coltsfoot, Tussilago farfara L. — rat in vivoView study →Reference 2Cao K et al. · 2016Sensitive determination of pyrrolizidine alkaloids in Tussilago farfara L. by field-amplified, sample-stacking, sweeping micellar electrokinetic chromatography — analyticalView study →}. It is also a major alkaloid of butterbur (Petasites hybridus), appearing in rhizome analyses with senecionine and seneciphylline ^{4Reference 4Aydın 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 →} and in the five-compound panels used to certify commercial butterbur extracts ^{5Reference 5Schenk A et al. · 2015UPLC TOF MS for sensitive quantification of naturally occurring pyrrolizidine alkaloids in Petasites hybridus extract (Ze 339) — analyticalView study →}.

Its environmental footprint follows the plants. In a Danish study of invasive butterbur, senkirkine was among the dominant alkaloids found not only in the plants but in the stream water and groundwater-well seepage around them ^{9Reference 9Kisielius V et al. · 2020The invasive butterbur contaminates stream and seepage water in groundwater wells with toxic pyrrolizidine alkaloids — analyticalView study →}.

Coltsfoot’s other pyrrolizidine, tussilagine, is a non-toxic necine-base alkaloid without the 1,2-unsaturation, and should not be confused with senkirkine — the presence of “pyrrolizidine alkaloids” in a plant says nothing until the subtype is known.

Discovery & Synthesis

Senkirkine was isolated and characterised in the mid-twentieth century as part of the broad survey of pyrrolizidine alkaloids driven by livestock poisoning, and it became significant in 1976, when the coltsfoot feeding study identified it as the probable carcinogen of a widely used cough herb ^{1Reference 1Hirono I et al. · 1976AnimalCarcinogenic activity of coltsfoot, Tussilago farfara L. — rat in vivoView study →}. Its mutagenicity was confirmed three years later in the then-new Ames test ^{6Reference 6Yamanaka H et al. · 1979In vitroMutagenicity of pyrrolizidine alkaloids in the Salmonella/mammalian-microsome test — in vitroView study →}.

There is no synthesis or manufacture of interest. Senkirkine is isolated from plant material as an analytical reference standard, and the technical effort around it is entirely detection — methods sensitive enough to find it at parts per billion in herbal extracts and at nanograms per litre in water ^{5,9Reference 5Schenk 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

Senkirkine is flagged toxic and carcinogen. It is a 1,2-unsaturated macrocyclic diester pyrrolizidine alkaloid, mutagenic on metabolic activation ^{6Reference 6Yamanaka H et al. · 1979In vitroMutagenicity of pyrrolizidine alkaloids in the Salmonella/mammalian-microsome test — in vitroView study →}, adduct-forming in rat liver ^{7Reference 7Xia Q et al. · 2013AnimalPyrrolizidine alkaloid-derived DNA adducts as a common biological biomarker of pyrrolizidine alkaloid-induced tumorigenicity — rat in vivoView study →}, and the compound named for coltsfoot’s rat liver-tumour result ^{1Reference 1Hirono I et al. · 1976AnimalCarcinogenic activity of coltsfoot, Tussilago farfara L. — rat in vivoView study →}.

The class assessment applies to it in full. There is no safe intake: the European evaluation of 1,2-unsaturated pyrrolizidine alkaloids works from a BMDL₁₀ of 237 µg/kg body weight per day and names herbal teas as the main dietary source ^{10Reference 10Dusemund B et al. · 2018ReviewRisk assessment of pyrrolizidine alkaloids in food of plant and animal origin — reviewView study →}, and a proposed acute reference dose of 1 µg/kg body weight per day has since been derived ^{11Reference 11Eckert 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 low enough to require parts-per-billion analytical methods ^{5Reference 5Schenk A et al. · 2015UPLC TOF MS for sensitive quantification of naturally occurring pyrrolizidine alkaloids in Petasites hybridus extract (Ze 339) — analyticalView study →}.

Two points specific to senkirkine are worth carrying. First, slow is not safe: its inactivity after a single cell exposure and full activity after fourteen days ^{3Reference 3Waizenegger 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 →} matches the exposure pattern of a herb taken daily, which is the wrong way round for reassurance. Second, the herb it defines is a cough remedy — coltsfoot has been used for inflamed airways for centuries, and this alkaloid is the reason that use is now restricted or reformulated in several countries. Whether a specific coltsfoot or butterbur product is acceptable depends on its measured alkaloid content, and that judgement belongs on the herb or product page.

Safety at a Glance

☠️ ToxicLiver risk

• Named as the carcinogen behind coltsfoot’s rat liver tumours — 8 of 12 rats developed haemangioendothelial sarcoma on a high-coltsfoot diet.
• Genotoxic on activation. Mutagenic in Ames TA100 with S9, and forms the pyrrolizidine class’s four signature DNA adducts in rat liver.
• Slower, not safer. Not cytotoxic to human liver cells after one exposure; fully cytotoxic after fourteen days of repeated dosing.
• No safe intake. Assessed with the 1,2-unsaturated pyrrolizidine class; proposed acute reference dose 1 µg/kg body weight per day.
• Depleted extracts are a different product. The butterbur extract Ze 339 showed no senkirkine down to a 2 ppb limit of quantification.

Dosage

There is no dose. No preparation should be taken to obtain senkirkine; the figures below are limits and measurements.

References

1. 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/
2. 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/
3. 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/
4. 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/
5. 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/
6. Yamanaka H, Nagao M, Sugimura T, et al. (1979). Mutagenicity of pyrrolizidine alkaloids in the Salmonella/mammalian-microsome test — in vitro. Mutat Res. https://pubmed.ncbi.nlm.nih.gov/390394/
7. Xia Q, Zhao Y, Von Tungeln LS, et al. (2013). Pyrrolizidine alkaloid-derived DNA adducts as a common biological biomarker of pyrrolizidine alkaloid-induced tumorigenicity — rat in vivo. Chem Res Toxicol. https://pubmed.ncbi.nlm.nih.gov/23937665/
8. 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/
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. 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/
11. 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/

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