Abstract
The tremorgenic mycotoxin penitrem A is produced by Penicillium species as a secondary metabolite on moldy food and feed. Dogs are sometimes exposed to penitrem A by consumption of spoiled food waste or fallen fruit. The lipophilic toxin crosses the blood-brain barrier and targets neuroreceptors and neurotransmitter release mechanisms in the central and peripheral nervous systems. Typical symptoms of penitrem A intoxication are periodical or continuous tremors, which can be passing, persistent or lethal, depending on the absorbed dose. There is presently no information on the biotransformation and toxicokinetics of penitrem A in dogs. The aim of the present study was therefore to identify potential metabolites of the toxin by performing in vitro biotransformation assays in dog liver microsomes. Analyses by liquid chromatography coupled to high-resolution mass spectrometry led to the provisional identification of eleven penitrem A phase I metabolites, which were tentatively characterized as various oxidation products. Furthermore, elimination parameters determined in in vitro assays run under linear kinetics were used for in vitro-to-in vivo extrapolation of the toxicokinetic data, predicting a maximal bioavailability of more than 50%. The metabolite profile detected in the in vitro assays was similar to that observed in the plasma of an intoxicated dog, confirming the predictive capability of the in vitro approach.
Highlights
Penitrem A (Figure 1) is a toxic secondary metabolite of Penicillium crustosum, a fungus adapted to all climate zones that occurs mainly on spoiled food and feed [1,2]
collision-induced dissociation (CID) resulted in sequential losses of water and acetone, and the mass spectra did not show any ions with significant signal intensities below m/z 500
While the principal product ion from CID was observed at m/z 558 [27], this ion was of medium intensity in the Higher-energy collision dissociation (HCD) HRMS/MS spectrum (Figure 2)
Summary
Penitrem A (Figure 1) is a toxic secondary metabolite of Penicillium crustosum, a fungus adapted to all climate zones that occurs mainly on spoiled food and feed [1,2]. Intoxication with penitrem A from the ingestion of moldy foodstuffs or contaminated grass causes neurological symptoms, in which the severity and persistence depend directly on the level of exposure [5]. The mycotoxin can pass through the blood-brain barrier into the central nervous system, where it affects the GABAergic neurotransmission, blocks potassium channels and causes cell death [6,7]. Neurological effects such as activity suppression, lethargy and cataleptic behavior can occur as early as 30 s after uptake, followed by irritability, hyperresponsiveness. The marine drugs astaxanthin and docosahexaenoic acid have shown some effectiveness in counter-acting penitrem A-related cytotoxicity when applied preventively, but a curative treatment after intoxication has not been developed [24]
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