Penitrem A and analogues: toxicokinetics, toxicodynamics including mechanism of action and clinical significance

Abstract

Penitrem A is a mycotoxin mainly produced by Penicillium crustosum, a fungal species occurring in all climate zones, ranging from tropical to arctic areas. P. crustosum produces a wide range of toxic metabolites, including penitrems, thomitrems and roquefortine C. The major metabolite, penitrem A, has been associated with several episodes of mycotoxicosis in dogs. The clinical symptoms of acute penitrem A intoxication include classical signs of neurotoxicity, such as tremors, convulsions, ataxia and nystagmus. The outcomes of penitrem A intoxication in animals range from total recovery to death, depending mainly on the level of exposure. Cases of suspected human mycotoxicosis following exposure to P. crustosum infected food, beer or inhalation of dust have also been reported. The toxicokinetics of penitrem A is scarcely studied. The toxin is rapidly absorbed, as demonstrated by the rapid onset of symptoms after exposure, but the absorption has not been quantified. Penitrem A is transported systemically after absorption and has been found in liver, kidney and brain as well as in serum and the gastrointestinal tract in exposed animals. Five phase I metabolites have been found in liver extracts of mice 60 min after oral exposure to penitrem A, while three metabolites were found after in vitro incubations with primary rat hepatocytes and rat liver microsomes. Only penitrem A was found in the brains of exposed mice or intoxicated dogs. The elimination has not been studied. Penitrem A is probably the main tremorgenic compound in Penicillium-infected food and feed commodities, since analogues had lower toxic potentials in comparative studies. Penitrem A affects the central as well as the peripheral nervous system. The toxin blocks the high-conductance Ca2+-activated potassium channels (BK) and impairs the GABAergic neurotransmission in the cerebellum. Animal poisoning by penitrem A is probably underdiagnosed due to a lack of knowledge among veterinarians.