Ptaquiloside is a norsesquiterpene glucoside produced by bracken ferns (majorly Pteridium aquilinum) during metabolism. It is identified to be the main carcinogen of the ferns and to be responsible for their biological effects, such as haemorrhagic disease and bright blindness in livestock and oesophageal, gastric cancer in humans. Ptaquiloside has an unstable chemical structure and acts as a DNA alkylating agent under physiological conditions. It was first isolated and characterized by Yamada and co-workers in 1983. The pure form ptaquiloside is a colorless amorphous compound. It is readily soluble in water and fairly soluble in ethyl acetate. Except in the plants, ptaquiloside has been detected in the milk and meat of affected livestock, as well as in the underground water and dry soil around bracken fern vegetation. The prevalence of ptaquiloside in daily sources along with its carcinogenic effects make it an increasing biological hazard in modern days.
Sources
In plants and food chains
The presence of ptaquiloside has been detected in a variety of ferns, including the species in the genera Pteridium (bracken), Pteris, Microlepia, and Hypolepis. Pteridium aquilinum (commonly known as bracken fern) is the most common ptaquiloside-containing fern with a wide geographical and ecological distribution. It is present in all continents from subtropic to subarctic areas. Bracken fern is a very adaptable plant and is capable of forming dense, rapidly expanding populations in course of the first phases of the ecological succession in forest cleanings and other disturbed rural areas. Its aggressive growth, characterized by an extensive rhizome system and rapidly growing fronds, sometimes enables it to be a dominant species in certain plant communities. The ptaquiloside content of bracken varies widely across species and changes with the part of the plant, the plant growing site and the collecting season. According to previous studies, the concentrations of ptaquiloside in bracken varied between 0 and 1% of the dry weight of the plant. Generally, ptaquiloside is found to occur in the highest concentrations in the young developing parts of bracken, such as the croziers and unfolding parts during the spring and early summer, while the concentrations of ptaquiloside in the rhizomes are rather low. However, studies on the concentrations of ptaquiloside in Danish bracken by Rasmussen et al. showed that the concentrations of ptaquiloside in the rhizomes were significantly higher than the previously reported values. Ptaquiloside can pass into the milk produced by bracken-fed cows and sheep. In 1996, Alonso-Amelot, Smith and co-workers found that ptaquiloside was excreted in milk at a concentration of 8.6 ± 1.2% of the amount ingested by a cow from bracken, and was linearly dose-dependent. On the basis of their experiments and the assumption that a person drinks 0.5 litres of milk daily, they estimated that this person might ingest about 10 mg of ptaquiloside per day, although only some of that amount will be absorbed. Ptaquiloside can also leach from the bracken leaves into water and soil. Numerous studies have reported the presence of ptaquiloside in the underground/surface water, and soil near bracken vegetation. The degradation speed of ptaquiloside in the soil is affected by the acidity, clay content, carbon content, temperature and presumably microbioactivity. Acidic condition (pH<4) and high temperature (at least 25 °C) facilitate ptaquiloside degradation, while the half-life of ptaquiloside in less acidic sandy soil is reported to be between 150 and 180 hours.
Ways of ptaquiloside exposure Main routes that can lead to human exposure to the toxic effects of bracken fern include ingestion of the plant (particularly the croziers and young fronds), inhalation of the airborne spores, consumption of the milk and meat of affected animals, and drinking ptaquiloside contaminated water.
Mechanism of action Ptaquiloside has unstable chemical structure and readily undergoes glucose liberation. The resulting ptaquilodienone is the active form of ptaquiloside and accounts for the observed biological effects. The cyclopropyl group in the dienone is highly reactive as an electrophile, not only because it is conjugated with the keto group, but because it also constitutes a cyclopropyl carbinol system, from which the facile formation of the stable non-classical cation is well-known.
General mechanism In acidic conditions, ptaquiloside gradually undergoes aromatization with the elimination of D-glucose to afford ptaquilosin, and finally pterosin B. Under weakly alkaline conditions, ptaquiloside and its aglycone ptaquilosin are converted into an unstable conjugated dienone intermediate. This ptaquilodienone is the activated form of ptaquiloside and is regarded as the ultimate carcinogen of bracken ferns. Due to the constitution of a cyclopropyl carbinol system, ptaquilodienone is a strong electrophile and acts as a powerful alkylating agent that reacts directly with biological nucleophiles including amino acids, nucleosides, and nucleotides under weakly acidic conditions at room temperature (as shown in the scheme below).
Under physiological conditions Under physiological conditions, ptaquiloside readily liberates glucose to produce the ptaquilodienone. The alkylation of amino acids with the dienone mostly takes place at the thiol group in cysteine, glutathione and methionine. The alkylation at the carboxylate group of each amino acid, forming the corresponding ester, is also observed to a small extent based on the previously reported literature. The dienone reacts with both adenine (majorly at N-3) and guanine (majorly at N-7) residues of DNA to form the DNA adducts. The alkylation induces spontaneous depurination and cleavage of DNA at adenine base site. In a model reaction with a deoxytetranucleotide (as shown on the right), a covalent adduct is found at a guanine residue and the N-glycosidic bond breaks to release the adduct. In 1998, Prakash, Smith and co-workers showed that the alkylation of adenine by ptaquiloside in codon 61 followed by depurination and error in the DNA synthesis resulted in the activation of H-ras proto-oncogene in the ileum of calves fed bracken.
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