Jacobine - one of the reasons behind the toxicity of ragwort

Jacobaea vulgaris, commonly known as ragwort or stinking willie, is a plant of the family Asteraceae. It is native to northern Eurasia, but it is widely distributed nowadays. It is considered a pest, as it spreads rapidly on roadsides, grasslands and forests clearings. Ragwort causes a great number of animal loses due to poisoning. In Senecio jacobea are found over thirty five pyrrolizidine alkaloids (PAs). The PAs are divided into four classes: senecionine, jacobine, erucifoline and otosenine-like PAs. Jacobine-like compounds are the most persistent and in highest amounts in the plant in certain chemotypes, representing up to 84% of the total content of PAs. The concentration of jacobine in the plant is up to 2.5 mg/g dry weight.

Figure 1. Structure of Jacobine (Source: Chemspider). Click image for more info and an interactive 3D model

Jacobine, is a macrocyclic ester characterized by an epoxide functional group. This functional group may inhibit the biotransformation and further detoxification of PAs by esterases. The molecule is present in two forms: as a free base or a N-oxide form, where the free base is the more toxic. However, the N-oxide is ingested and metabolized by Cytochrome P450 to pyrro intermediates, which are unstable and toxic. The toxic effects are due to the interference with several receptors that affects the muscular and nervous systems.

This plant is responsible for more number of poisonings and deaths of cattle than any other plant in the UK. The negative effects are especially severe in cattle and horses. In contrary, sheeps presents detoxifying mechanisms of PAs. The detoxifying capacity of different ovine ruminants is different, presenting different biotransformation rates between species. This is due to the different bacterial communities in the gut of different animals, being the bacteria responsible of the biotransformation of PAs. It has been suggested that the composition of the bacterial community, and specially the presence of gram-positive bacteria, have a great influence on the biotransformation on PAs. Moreover, antibiotics present in feed additives might inhibit the biotransformation of PAs, hence reducing the detoxifying mechanism of the animal.

A recent study found out that there is horizontal transfer of natural products between plant species. The PAs can be leached into the soil from living and decaying source plants. This studied suggested that the uptake of PAs by other plant species might be more common than expected. The PAs after being incorporated are translocated into the leaves. This might be the reason of the presence of jacobine and other PAs food products such as herbal teas or spices.

CAS no: 6870-67-3

SMILES: CC1CC2(C(O2)C)C(=O)OC3CCN4C3C(=CC4)COC(=O)C1(C)O

References:

• Macel, M., Vrieling, K., & Klinkhamer, P. G. (2004). Variation in pyrrolizidine alkaloid patterns of Senecio jacobaea. Phytochemistry, 65(7), 865-873.
• Nowak, M., Wittke, C., Lederer, I., Klier, B., Kleinwächter, M., & Selmar, D. (2016). Interspecific transfer of pyrrolizidine alkaloids: an unconsidered source of contaminations of phytopharmaceuticals and plant derived commodities. Food chemistry, 213, 163-168.
• Nuringtyas, T. R., Verpoorte, R., Klinkhamer, P. G., van Oers, M. M., & Leiss, K. A. (2014). Toxicity of pyrrolizidine alkaloids to Spodoptera exigua using insect cell lines and injection bioassays. Journal of chemical ecology, 40(6), 609-616.
• Schmeller, T., El-Shazly, A., & Wink, M. (1997). Allelochemical activities of pyrrolizidine alkaloids: interactions with neuroreceptors and acetylcholine related enzymes. Journal of chemical ecology, 23(2), 399-416.

Figures:

• https://weedwise.conservationdistrict.org
• http://www.chemspider.com/Chemical-Structure.391085.html