[1차 표준물질/Primary Reference Standards] Pyrrolizidine Alkaloids (피롤리지딘 알칼로이드)_Phyproof PhytoLab - 코아사이언스

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Pyrrolizidine alkaloids

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As one of the leading manufacturers internationally, PhytoLab offers over 1,400 extensively documented herbal reference substances of all classes of natural compounds. Our portfolio currently includes a total of 28 pyrrolizidine alkaloids, 26 pyrrolizidine alkaloid N-oxides and one necine base. Most of our pyrrolizidine alkaloids reference substances are certified as primary reference standards.

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Occurrence

Pyrrolizidine alkaloids are common secondary plant metabolites that - until today - have been described in more than 350 plant species. According to chemotaxonomic estimates it is suspected that pyrrolizidine alkaloids occur in more than 6000 plant species from at least twelve higher plant families (Bunchorntavakul C. and Reddy K. R. (2013). Review article: herbal and dietary supplement hepatotoxicity. Alimentary Pharmacology & Therapeutics 37: 3-17; Teuscher E., Melzig M. F., Lindequist U. (2004). Biogene Arzneimittel. Ein Lehrbuch der Pharmazeutischen Biologie. Vol. 6, Wissenschaftliche Verlagsgesellschaft, Stuttgart). It has been estimated that about 3 % of all flowering plants from all continents contain pyrrolizidine alkaloids. More than 660 pyrrolizidine alkaloids and pyrrolizidine alkaloid N-oxides with varying toxic properties have been identified so far. Pyrrolizidine alkaloids are therefore probably the most widespread group of natural substances with toxicological relevance for humans and animals. Plants produce these compounds as a defence against herbivory by insects and mammalians. Due to their widespread occurrence, pyrrolizidine alkaloids are well known contaminants of various foodstuffs such as leaf lettuces, cereals, spices, teas, herbal teas, and honey. Animal feedstuff can be affected as well. The most common source for the pyrrolizidine alkaloids are weeds from the families of the Asteraceae (e.g. genus Senecio, known as groundsel or ragwort), Boraginaceae (most genera) and Fabaceae (e.g. genus Crotalaria, known as rattlepods). About 95% of all pyrrolizidine alkaloids occur in the three aforementioned families as well as in Orchidaceae and Apocynaceae. Honey can be contaminated with pyrrolizidine alkaloids if plants from these and other families are visited by the honey bees.

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Chemical structure and classification

From a chemical point of view pyrrolizidine alkaloids are mono- or diesters of 1-hydroxymethyl pyrrolizidine (necine base) and aliphatic mono- or dicarboxylic acids (necic acids). Otonecine-type, platynecine-type, and the C7-diastereomeric retronecine-type and heliotridine-type pyrrolizidine alkaloids are distinguished, their structure depending on the substitution pattern of the necine base.

Besides the linear mono- and diesters also cyclic diesters can occur, if esterification occurs with both carboxyl groups of a dicarboxylic acid. Necic acids are typically branched mono- or dicarboxylic acids with a chainlength of 5-10 carbon atoms carrying various substituents. Their names are sometimes related to the corresponding pyrrolizidine alkaloid, such as echimidinic, heliotrinic, integerrinecic, jacobinecic, jaconinecic, junceic, lasiocarpic, monocrotalic, retronecic, riddelliic, sceleranecic, senecinic, seneciphyllinic, senecivernic and trichodesmic acid. Other necic acids are acetic, angelic, isatinecic, trachelanthic and viridifloric acid. Biosynthetically they are derived from amino acids.

Pyrrolizidine alkaloids can also be grouped into subclasses according to their taxonomic occurrence:

• Senecionine-type pyrrolizidine alkaloids are the largest and most diverse class and the group consists of mostly cyclic diesters. Members of this subclass are generic for species of the Asteraceae tribe Senecioneae and are also found in Crotalaria species (Fabaceae)
• Crotalaria spp. also contain monocrotaline-type pyrrolizidine alkaloids that are characterised by eleven-membered ring ring instead of the twelve-membered ring found in cyclic Senecionine-type pyrrolizidine alkaloids
• Lycopsamine-type pyrrolizidine alkaloids are open mono- or diesters. They contain species-specific either retronecine or heliotridine as the necine base. Lycopsamine-type pyrrolizidine alkaloids occur in Asteraceae (tribe Eupatorieae), the Boraginaceae and the Apocynaceae

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phyproof® Pyrrolizidine Alkaloid Reference Substances

Pyrrolizidine alkaloid	Necine base	Necic acid	Overall structure	Subclass
7-Acetylintermedine and N-oxide	Retronecine	(+)-Trachelanthic/Acetic	Open diester	Lycopsamine-type
7-Acetyllycopsamine and N-oxide	Retronecine	(-)-Viridifloric/Acetic	Open diester	Lycopsamine-type
Echimidine and N-oxide	Retronecine	Echimidinic/Angelic	Open diester	Lycopsamine-type
Echinatine and N-oxide	Heliotridine	(-)-Viridifloric	Monoester	Lycopsamine-type
Echiumine and N-oxide	Retronecine	(+)-Trachelanthic/Angelic	Open diester	Lycopsamine-type
Erucifoline and N-oxide	Retronecine	Erucifolinecic	Cyclic diester	Senecionine-type
Europine and N-oxide	Heliotridine	Lasiocarpic	Monoester	Lycopsamine-type
Heliosupine and N-oxide	Heliotridine	Echimidinic/Angelic	Open diester	Lycopsamine-type
Heliotrine and N-oxide	Heliotridine	Heliotrinic	Monoester	Lycopsamine-type
Indicine and N-oxide	Retronecine	(-)-Trachelanthic	Monoester	Lycopsamine-type
Integerrimine and N-oxide	Retronecine	Integerrinecic	Cyclic diester	Senecionine-type
Intermedine and N-oxide	Retronecine	(+)-Trachelanthic	Monoester	Lycopsamine-type
Jacobine and N-oxide	Retronecine	Jacobinecic	Cyclic diester	Senecionine-type
Jaconine	Retronecine	Jaconinecic	Cyclic diester	Senecionine-type
Junceine and N-oxide	Retronecine	Junceic	Cyclic diester	Senecionine-type
Lasiocarpine and N-oxide	Heliotridine	Lasiocarpic/Angelic	Open diester	Lycopsamine-type
Lycopsamine and N-oxide	Retronecine	(-)-Viridifloric	Monoester	Lycopsamine-type
Monocrotaline and N-oxide	Retronecine	Monocrotalic	Cyclic diester	Monocrotaline-type
Retronecine	Retronecine	-	necine base	-
Retrorsine and N-oxide	Retronecine	Isatinecic	Cyclic diester	Senecionine-type
Riddelliine and N-oxide	Retronecine	Riddeliic	Cyclic diester	Senecionine-type
Rinderine and N-oxide	Heliotridine	(+)-Trachelanthic	Monoester	Lycopsamine-type
Sceleratine and N-oxide	Retronecine	Sceleranecic	Cyclic diester	Senecionine-type
Senecionine and N-oxide	Retronecine	Senecic	Cyclic diester	Senecionine-type
Seneciphylline and N-oxide	Retronecine	Seneciphyllic	Cyclic diester	Senecionine-type
Senecivernine and N-oxide	Retronecine	Senecivernic	Cyclic diester	Senecionine-type
Senkirkin	Otonecine	Senecic	Cyclic diester	Senecionine-type
Trichodesmine and N-oxide	Retronecine	Trichodesmic	Cyclic diester	Monocrotaline-type
Usaramine and N-oxide	Retronecine	Retronecic	Cyclic diester	Senecionine-type

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Toxicity

A prerequisite for the toxicity is an 1,2-unsaturated necine core structure that forms an ester with at least one branched C5-carboxylic acid. Pyrrolizidine alkaloids with these structural characteristics have been found to be genotoxic and carcinogenic in animal experiments. The saturated platynecine-type pyrrolizidine alkaloids are therefore the least toxic. In larger quantities pyrrolizidine alkaloids can also cause acute and chronic liver damage. It was found that the toxicity of monoesters of the hydroxymethyl group of the necine base is enhanced if a second hydroxyl group is attached to C-7 of the necine core. The toxicity is further intensified if a diester involving the second hydroxyl group is formed. The most toxic properties are attributed to cyclic diesters.

Except for otonecine-type pyrrolizidine alkaloids plants usually contain a mixture of pyrrolizidine alkaloids and their N-oxides. A comparable toxicity is attributed to both forms upon oral ingestion as the N-oxides are metabolized by reductases to the underlying alkaloid. Further metabolisation of 1,2-unsaturated pyrrolizidine alkaloids by certain liver enzymes (cytochrome P450 monooxygenases) results in highly reactive pyrrole esters that can form DNA and protein adducts, that are ultimately responsible for the toxic activity.

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Legal provisions

Pyrrolizidine alkaloid contamination is a relevant issue equally for herbal medicinal products as for food and feed. Since pyrrolizidine alkaloid contamination is difficult to control, limits cannot be derived solely on the basis of toxicological calculations. Strongly triggered by findings of the German Federal Institute for Risk Assessment (BfR) on pyrrolizidine alkaloid occurrence in tea and herbal/fruit infusions in 2013, occurrence data have been collected both by industry associations and official control labs in order to establish a sufficiently realistic and representative picture of overall pyrrolizidine alkaloid exposure through food and herbal medicinal products. During the same time collectors, growers and producers of herbs/herbal products have put huge effort into root cause analysis and measures for improvement. These efforts have recently enabled regulators to establish sufficiently protective however reasonably achievable pyrrolizidine alkaloid limits for herbal medicinal products (Public statement on the use of herbal medicinal products containing toxic, unsaturated pyrrolizidine alkaloids (PAs) including recommendations regarding contamination of herbal medicinal products with PAs. EMA/HMPC/893108/2011 Rev. 1, 07 July 2021) and for important pyrrolizidine alkaloid-susceptible food commodities/categories (COMMISSION REGULATION (EU) 2020/2040 of 11 December 2020 amending Regulation (EC) No 1881/2006 as regards maximum levels of pyrrolizidine alkaloids in certain foodstuffs. Official Journal of the European Union, 14.12.2020) as shown in the table below.

Limits for pyrrolizidine alkaloids in food according to Regulation (EU) 2020/2040

​	Foodstuffs	Maximum level (μg/kg)
8.4	Pyrrolizidine alkaloids	​
8.4.1	Herbal infusions (dried product) with the exception of the herbal infusions referred to in 8.4.2 and 8.4.4	200
8.4.2	Herbal infusions of rooibos, anise (Pimpinella anisum), lemon balm, chamomile, thyme, peppermint, lemon verbena (dried product) and mixtures exclusively composed of these dried herbs with the exception of the herbal infusions referred to in 8.4.4	400
8.4.3	Tea (Camellia sinensis) and flavoured tea (Camellia sinensis) (dried product) with the exception of the tea and flavoured tea referred to in 8.4.4	150
8.4.4	Tea (Camellia sinensis), flavoured tea (Camellia sinensis) and herbal infusions for infants and young children (dried product)	75
8.4.5	Tea (Camellia sinensis), flavoured tea (Camellia sinensis) and herbal infusions for infants and young children (liquid)	1,0
8.4.6	Food supplements containing herbal ingredients including extracts with the exception of the food supplements referred to in 8.4.7	400
8.4.7	Pollen based food supplements, pollen and pollen products	500
8.4.8	Borage leaves (fresh, frozen) placed on the market for the final consumer	750
8.4.9	Dried herbs with the exception of the dried herbs referred to in 8.4.10	400
8.4.10	Borage, lovage, marjoram and oregano (dried) and mixtures exclusively composed of these dried herbs	1000
8.4.11	Cumin seeds (seed spice)	400

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Recommendation

For a reliable quantitative analysis of pyrrolizidine alkaloids and their N-oxides well characterized reference substances are essential. Because of great variances in response factors (e.g. in LC-MS analysis) as well as in toxicity, the quantitative analysis of individual pyrrolizidine alkaloids is preferred over a non-selective sum method. Currently we offer a total of 55 pyrrolizidine alkaloids, including pyrrolizidine alkaloid N-oxides and necine bases, all of them supplied together with a comprehensive certificate of analysis.

For up-to-date information on prices and specifications please check the product detail pages below!

55 products

7-Acetylintermedine 83759

7-Acetylintermedine N-oxide 83795

7-Acetyllycopsamine N-oxide 84275

7-Acetyllycopsamine hydrochloride 85874

Echimidine perchlorate 86541

Echimidine N-oxide 83590

Echinatine N-oxide 84093

Echinatine sulfate 86118

Echiumine 83749

Echiumine N-oxide 84164

Erucifoline 83432

Erucifoline N-oxide 83433

Europine hydrochloride 83237

Europine N-oxide 83238

Heliosupine sulfate 86678

Heliosupine N-oxide 84092

Heliotrine 80403

Heliotrine N-oxide 83236

Indicine hydrochloride 83234

Indicine N-oxide 83235

Integerrimine 83968

Integerrimine N-oxide 83969

Intermedine 82424

Intermedine N-oxide 83446

Jacobine 83434

Jacobine N-oxide 83435

Jaconine 83970

Junceine 85643

Junceine N-oxide 85644

Lasiocarpine 80412

Lasiocarpine N-oxide 83220

Lycopsamine 89726

Lycopsamine N-oxide 83447

Monocrotaline 89251

Monocrotaline N-oxide 82629

Retronecine 83901

Retrorsine 89775

Retrorsine N-oxide 82630

Riddelliine 84102

Riddelliine N-oxide 84103

Rinderine 84162

Rinderine N-oxide 84163

Sceleratine 84073

Sceleratine N-oxide 84074

Senecionine 89789

Senecionine N-oxide 82631

Seneciphylline 89275

Seneciphylline N-oxide 82632

Senecivernine 83436

Senecivernine N-oxide 83437

Senkirkin 89274

Trichodesmine 83438

Trichodesmine N-oxide 84738

Usaramine 84274

Usaramine N-oxide 84703

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코아사이언스 coresciences PhytoLab GmbH & Co. KG 독일 한국 대리점 korea biochemical high quality phytochemicals reference standards analytical standard natural active ingredients products 표준품 기능성분 표준물질 지표성분 주성분 유효성분 순품 한방 한약 생약 천연물 신약 식물 유래 천연화합물 천연물 primary reference substance primary reference standard 일차 표준물질 1차 표준품 1차 표준물질 1차 지표물질 식품 검사 식물독소 자연독소 독성물질 피롤리지딘 알칼로이드 Pyrrolizidine alkaloid 벌꿀 화분 제품 꽃가루 잔류 유해물질 식품의약품안전처 향신료 버섯 간·유전 독성 발암 수입 제품 검사 식품 안전 검사 피롤리지딘알칼로이드