Unravelling the sanitary impact of Annonaceous acetogenins: A dereplicative approach

Atypical parkinsonian syndromes are abnormally frequent in the French West Indies. They were linked epidemiologically to the consumption, for alimentary and medicinal means, of plants of the Annonaceae family, suggesting a possible toxic aetiology, as emphasized by the French food safety agency (Anses) [1]. These plants contain Annonaceous acetogenins, such as annonacin. These inhibitors of mitochondrial complex I proved to be neurotoxic in several in vitro and in vivo paradigms [2]. A particular emphasis was given to the influence of acetogenins on the distribution of the tau protein, which aggregates in several neurodegenerative diseases: Recently obtained in vivo (per os) data will be presented. Our actual efforts are focused on chemical analysis of sources of exposure to acetogenins, i.e. fruit pulps and fruit juices of the main edible Annona species (A. cherimolia, A. muricata, A. squamosa...). Methodological development was performed using HPLC-ESI-LTQ-Orbitrap®, HPLC-ESI-TQ and HPLC-ESI-Q-TOF as tools for various purposes. Note worthily, the post-chromatographic use of lithium allowed direct apprehension of a vast and underestimated diversity of these molecules in crude extracts [3]. A chemometric approach is now being developed. Nevertheless, pharmacokinetic parameters of acetogenins are unknown and are likely to constitute key-factors for inter-individual variability in Human. A phase I metabolic study was conducted with annonacin [4]. Study of the bioavailability of this molecule was also performed, in the Rat. Here again, the input of hyphenated methods proved crucial for both detection and quantification of the molecule and its metabolites. The wealth of data obtained so far by our group and our collaborators strongly supports Annonaceae as a risk factor for sporadic parkinsonism/dementia.

References:

[1] Camuzat A, et al. The PSP-associated MAPT H1 subhaplotype in Guadeloupean atypical parkinsonism. Mov.Disord. 2008, 23 (16), 2384 – 2391; Afssa, Saisine 2008-SA-0171, 28th april 2010.

[2] Höllerhage M., et al. Natural lipophilic inhibitors of mitochondrial complex I are candidate toxins for sporadic tau pathologies. Exp. Neurol., 2009, 220, 133 – 142; Yamada E.S., et al. Annonacin, a natural lipophilic mitochondrial complex I inhibitor, increases phophorylation of tau in the brain of FTDP-17 transgenic mice. Exp. Neurol., 2014, 253,113 – 125.

[3] Le Ven J., et al. Comprehensive characterization of Annonaceous acetogenins within a complex extract by HPLC-ESI-LTQ-Orbitrap® using post-column lithium infusion. J. Mass Spectrom., 2012, 47, 1500 – 1509.

[4] Le Ven J., et al. Identification of the environmental neurotoxins Annonaceous acetogenins in an Annona cherimola Mill. alcoholic beverage using HPLC-ESI-LTQ-Orbitrap®. Submitted to J. Agric. Food Chem.