Abstract
BackgroundIngestion of the poisonous weed ragwort (Senecio jacobea) by horses leads to irreversible liver damage. The principal toxins of ragwort are the pyrrolizidine alkaloids that are rapidly metabolised to highly reactive and cytotoxic pyrroles, which can escape into the circulation and bind to proteins. In this study a non-invasive in vitro model system has been developed to investigate whether pyrrole toxins induce specific modifications of equine blood proteins that are detectable by proteomic methods.ResultsOne dimensional gel electrophoresis revealed a significant alteration in the equine plasma protein profile following pyrrole exposure and the formation of a high molecular weight protein aggregate. Using mass spectrometry and confirmation by western blotting the major components of this aggregate were identified as fibrinogen, serum albumin and transferrin.ConclusionThese findings demonstrate that pyrrolic metabolites can modify equine plasma proteins. The high molecular weight aggregate may result from extensive inter- and intra-molecular cross-linking of fibrinogen with the pyrrole. This model has the potential to form the basis of a novel proteomic strategy aimed at identifying surrogate protein biomarkers of ragwort exposure in horses and other livestock.
Highlights
Ingestion of the poisonous weed ragwort (Senecio jacobea) by horses leads to irreversible liver damage
Following ingestion of ragwort the pyrrolizidine alkaloids are absorbed from the gastrointestinal tract and pass to the liver where they can be rapidly metabolised by the cytochrome P450 system to reactive and cytotoxic pyrroles [8,9] (Figure 1)
The pyrrolic metabolites bind to liver macromolecules such as DNA, eliciting cell injury [10,11] but they can escape into the circulation where they react with the thiol groups of cysteine residues of blood proteins [12,13]
Summary
Ingestion of the poisonous weed ragwort (Senecio jacobea) by horses leads to irreversible liver damage. The pyrrolic metabolites bind to liver macromolecules such as DNA, eliciting cell injury [10,11] but they can escape into the circulation where they react with the thiol groups of cysteine residues of blood proteins [12,13] The persistence of these adducts formed the basis of one chemical analysis that was developed over a decade ago [14,15]. Haemoglobin thioesters were treated with ethanolic silver nitrate under acidic conditions, releasing a diethoxyether form of the bound pyrrole that can be identified by thin-layer chromatography, gas chromatography or high performance liquid chromatography This approach has been used to confirm ragwort poisoning in horses [16], cattle [17] and yaks [18] but has not been adopted widely
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