Pyrrolizidine alkaloids (2018)

For pharmacy students

1. Ph. D. Ahmed Metwaly

3. The bicyclic pyrrolizidine nucleus is formed by the utilization of two moles of ornithine and this
pathway is accomplished via the intermediate putrescine.

4. ▪In nature, the pyrrolizidine alkaloids have a relatively broad stretch of distribution, but are
specifically present in certain genera of the
Leguminosae/Fabaceae (e.g., Crotalaria);
the Compositae/Asteraceae (e.g., Senecio);
and the Boraginaceae(e.g., Heliotropium, Symphytum, and Cynoglossum).
▪The alkaloids present often in the seeds and flowering parts of the plant.
▪Broadly speaking the pyrrolizidine bases do not occur in their free form, but are mostly found as
esters with rare mono-or di-basic acids, the necicacids.
▪Necic acids are mono-or dicarboxylic acids with branched carbon chains composed of 5-10
carbon atoms.
▪The two important alkaloids of this category are, namely:
▪Retronecineand Senecionine, which shall be discussed :

5. ▪PAs are toxins exclusively biosynthesisedby plants. They are typical plant
secondary metabolites against herbivores. It has been estimated that
approximately 6000 plant species world wide, representing 3 % of all flowering
plants, may contain pyrrolizidine alkaloids.
▪To date, approximately 600 different PAs are known.

6. ▪A double bond at the C-1 and C-2 positions determines the hepatotoxicity of these alkaloids. In the
absence of a double bond, no metabolic activation to the pyrrole nucleus, which induces the
hepatotoxic or genotoxic actions, was observed.
▪Pyrrolizidine alkaloids often occur as N-oxides (except for the otonecine)
▪The oral intake of unsaturated PAs is limited to 0.35 μg/day up to 14 days for adults, and for the
representatives of sensitive groups, e.g., children: 0.007 μgPAs/kg body weight (bw), to prevent the
occurrence of side effects.
▪The animal toxicity of these compounds is also significant and led to a thorough examination of
their influence on grazing in animals. The effects of a single administration of PAs containing plants
may progress to advanced liver disease, cirrhosis, or tumors in animals. Pigs and poultry are much
more susceptible than cattle and horses, whereas sheep and goats are found to be relatively
resistant to pyrrolizidine alkaloids evoked toxicity.
▪Contamination of foods or food supplements with PAs is commonly reported due to the structural
variety of these alkaloids.

8. ▪In general, PAs show either no or low acute toxicity; but they can undergo a 3-step metabolic
toxicationprocess leading to alkylating agents. This process takes place in the human or
animal liver and this organ is therefore the first target organ for the intoxication.
▪PAs can show mutagenic, genotoxic, cancerogenic and fetotoxic potential

9. ▪Although these alkaloids have at present no great medicinal significance they are important in that
they constitute the poisonous hepatotoxic constituents of plants of the genus Senecio(Compositae),
well-known for their toxicity to livestock. Some of the alkaloids also show carcinogenic and
mutagenic properties and have caused concern in that they occur in small quantities in some herbal
products such as comfrey (Boraginaceae) and coltsfoot (Compositae).
These alkaloids are known to have an ecological role in some species of butterfly affording protection
to some and converting to female flight arrestantsin others.
The hepatotoxic properties are believed to arise by breakdown of the alkaloids in the liver to strongly
alkylating pyrrole esters.
Pyrrolizidine alkaloids were found to contaminate such human food sources as wheat,
milk, and honey

13. ▪Retronecine The most common base portion of the
pyrrolizidine alkaloids is retronecine.
▪The ‘Necine’ bases are 1-methylpyrrolizidines of
different stereochemical configurations and degree
of hydroxylation.
▪Biological Source It is obtained from the herbs of
Heliotropium europaeumL. (Boraginaceae)

14. (1R-trans)-2, 3, 5, 7, a-Tetrahydro-1-hydroxy-1 H-pyrrolizine-7-methanol; (C8H13NO2).

15. ▪Characteristic Features
▪1. It is obtained as crystals from acetone having mp119-120°C.
▪Uses
▪1. The plant is used for cancer and is popularly known as “HerbeDu Cancer” in
Europe.
▪2. It is also used for snakebite and scorpion stings.

16. ▪Synonym Aureine;
▪Biological Source The hepatotoxic alkaloid is obtained from the whole plant of
Seneciovulgaris L. (Compositae);
▪weed of Senecioaureus L. (Asteraceae)
▪and prebloomingplant of TussilagofarfaraL. (Asteraceae)

17. 12-Hydroxysenecionan-11, 16-dione; (C18H25NO5)

18. ▪Characteristic Features
▪It is obtained as plates having mp236°C and a bitter taste.
▪It is practically insoluble in water; freely soluble in chloroform; and slightly soluble
in ether and ethanol.
▪Uses
▪1. It is used as an excellent drug to control pulmonary hemorrhage.

20. ▪Indicine N-oxide isolated from Heliotropium indicum
▪Indicine N-oxide shows an antitumor activity. In early clinical studies the possibility of using it for
the treatment of leukemia and tumors was discussed.
▪Since the compound exhibited promising cytotoxic activity, it underwent preclinical and clinical
trials in the past for the treatment of acute leukemia of childhood
▪Cytotoxicity of INO is due its DNA damaging activities and its inhibitory effects on the assembly
of tubulin into microtubules
▪But severe toxic side-effects showed that a therapy with indicine-N-oxide was not justified

22. Ph. D. Ahmed M. Metwaly
Assistant professor, Pharmacognosy
department,
Faculty of Pharmacy, Al-Azhar University.
[email protected]