Pyrrolizidine alkaloid
Their use dates back centuries and is intertwined with the discovery, understanding, and eventual recognition of their toxicity on humans and animals.
For example, herbs containing PAs were used in traditional Chinese medicine and by Native American tribes for their purported therapeutic properties.
[8] In the early to mid-20th century, researchers began to observe and document cases of livestock poisoning linked to the consumption of PA-containing plants.
[11] These regulations aim to protect human and animal health by minimizing PA exposure and mitigating the risk of toxicity.
[12] Additionally, efforts to raise awareness among healthcare professionals, herbal product manufacturers, and the general public about the risks of PA exposure are ongoing.
PAs are a group of naturally occurring compounds found in a wide range of plant species.
These alkaloids are secondary metabolites synthesized by plants primarily as a defense mechanism against herbivores, insects, and pathogens.
Desaturation and hydroxylation ultimately form retronecine, which is acylated with an activated necic acid, for instance with senecyl-CoA2 as in the example shown below.
[14] PAs are compounds made up of a necine base, a double five-membered ring with a nitrogen atom in the middle, and one or two carboxylic esters called necic acids.
Among the possibilities are mono-esters, like Floridine and Heliotrine, and di-esters either with an open or closed ring structure, like Usaramine and Lasiocarpine.
A flexible strategy would be to start with a Boc (tert-Butoxycarbonyl) protected pyrrole molecule and use specific reaction for synthesis into the desired compound.
[19] PAs are commonly introduced into the body via oral ingestion through contaminated food or traditional medicine, notably borage leaf, comfrey and coltsfoot.
Here esterases can hydrolyze the PAs to reduce the compound into its necine acids and bases, both forms are non-toxic for humans and do not damage the body.
However, cytochrome P450 (CYP450) also metabolizes PAs, this enzyme can form pyrrolic esters (EPy), these are hepatotoxic due to their high reactivity.
The electrophilic nature of pyrroles makes it an easy target for nucleophilic attack from nucleic acids and protein.
This metabolic process leads to the formation of reactive intermediates, such as pyrrolic metabolites, which can covalently bind to proteins in the liver, forming pyrrole-protein adducts.
These adducts can induce mutations and DNA damage, increasing the risk of cancer development and other adverse health effects.
For example, retronecine-type PAs like monocrotaline are known to be highly hepatotoxic, while other types may exhibit lower toxicity or different toxicological profiles.
Retronecine derivatives have been found slow the growth rate of several strains of the fungus Fusarium oxysporum.
Several PAs have been found with significant inhibition of growth in the following viruses: coxsackie, poliomyelitis, measles, and vesicular stomatitis.
PAs like senecionine, integerrimine, retrorsine, usaramine and seneciphylline have been shown to cause an increase in both the levels of gastrin and the expression of epidermal growth factor (EGF).
