Human toxicity pyrrolizidine alkaloids

Pyrrolizidine alkaloids (PAs) constitute a class of plant toxin associated with disease in humans and animals. They are found in a wide variety of plant species in the world and it is estimated that 3% of the world s flowering plants contain toxic pyrrolizidine alkaloids. 

The N-oxide of indicine (49) exhibits anti-tumour activity in experimental tumour systems, without some of the toxic effects associated with other pyrrolizidine alkaloids. The N-oxides of echinatine and europine show similar anti-tumour activity against P 388 lymphocytic leukaemia tumours.23 Indicine N-oxide is metabolized to the free base in rabbits and humans,62 although the N-oxide is the more active anti-tumour agent. It has been suggested that the conversion of indicine N-oxide into indicine is not essential for its anti-tumour activity.63 Indicine N-oxide is the first pyrrolizidine alkaloid to be tested as an anti-tumour agent in humans. The toxicity and pharmacokinetics of this compound have been studied in 29 patients with advanced cancers.64 The major toxic effect was myelosuppression, but acute liver damage was not observed. 

Huxtable RJ (1989) Human health implications of pyrrolizidine alkaloids and herbs containing them. In Cheeke PR (ed) Toxicants of plant origin, vol 1. CRC lYess, Boca Raton, pp 42-86... 

Pyrrolizidine alkaloids poison animals grazing on toxic wild plants and those fed contaminated feed, causing economic losses. They poison humans through deliberate consumption of certain foods and herbal medicines and through consumption of food contaminated by wild plants, such as via transport of the toxins by bees into honey. Analytical methods are required for different purposes - to detect the presence of pyrrolizidine alkaloids, to quantify the total level of the toxins, or to measure the quantity of individual compounds. The task is made more challenging by the variety of PAs, their widespread nature and their different forms. Analytical methods are based on color reactions, enzyme linked immunosorbent assays (ELlSAs), spectroscopy, and the full range of chromatographic techniques. A lack of reference standards and... 

Wiedenfeld H, John Edgar J. Toxicity of pyrrolizidine alkaloids to humans and ruminants. Phytochem Rev. 2011 10 137-151. 

The iV-oxide of indicine (100) does disply anti-tumor activity with less toxic effects than related pyrrolizidine alkaloids it has recently been tested on humans 176). Some semi-synthetic quaternary pyrrolizidine derivatives block neuromuscular transmissions, and their synthesis and biological activities have recently been reviewed 19, 261). 

Quinolizidine alkaloids are non-toxic to the legumes which produce them. On the other hand, the quinolizidine alkaloids can be toxic and in some cases very toxic to other organisms. The biotoxicity of alkaloids has for some time been considered to be connected with their bitter taste" ° ". The quinolizidine alkaloids are certainly bitter in taste to humans. However, not all alkaloids are. Literature states that some pyrrolizidine and indolizidine alkaloids are not bitter in their pure forms" Furthermore, there are many non-alkaloid compounds, such as flavonoids, that are bitter in taste but non-toxic. Therefore, although quinolizidine alkaloids are bitter, the connection between biotoxicity and bitter taste is not absolute. 

Additional studies have shown that the oxidation of alkaloid to its N-oxide occurs and competes with pyrrole formation. N-oxides when administered intravenously to rats or when treated with liver microsomal enzymes are not converted to pyrroles. Hence they are non-toxic in the liver, and, by their highly hydrophilic nature, provide a pathway for detoxification. When administered orally to rats and sheep however, N-oxides are converted in the rumen (sheep) or gut (rats) to the parent alkaloids which are then metabolized in the liver causing the normal toxic sequelae. The toxicity (or lack thereof) of the pyrrolizidine N-oxides depends on whether or not they are reduced vivo before reaching the liver (61). After intravenous administration of indicine N-oxide to human cancer patients, free alkaloid has been detected in the blood and subsequent liver damage has been observed (55). 

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