Effet chez le porcelet d'une exposition à un régime co-contaminé en ...

TRAVAIL EXPERIMENTAL2002). Removal of the tricarballylic acids, which leads to HFB1, diminishes the potency of ceramidesynthase inhibition, and therefore the accumulation of sphingoid bases. In the current experiment,we may suppose that ceramide synthase inhibition did not occur, as displayed by the Sa/So ratio,either in plasma samples or in liver samples. This indicated that the TCA moieties are required formaximal inhibition of the enzyme. Our results are in agreement with studies which showed that HFB1was at least tenfold less potent compared to FB1 (Norred et al., 1992; Flynn et al., 1997; van derWesthuizen et al., 1998; Howard et al., 2002; Collins et al., 2006; Voss et al., 2009). As mentioned byVoss et al. (1998), increased liver Sa/So ratio is directly correlated with the increased of serumchemical indicators, leading to hepatotoxicity. This observation confirms our results on FB1 andHFB1.However, some findings showed that HFB1 becomes not only an inhibitor but also a substrate foracylation by ceramide synthase (Humpf et al., 1998; Abou-Karam et al., 2004; Seiferlein et al., 2007).This observation was firstly reported in HT29 cells (Humpf et al., 1998), where FB1 was notdetectably acylated on contrary to HFB1. The author suggested at this moment that the TCA of FB1occupy the acyl-CoA binding site and thereby block access of this co-substrate. Therefore, theremoval of TCA allowed to HFB1 to be acylated, and the first acylation observed was in presence ofpalmitoyl-CoA which led to the formation of N-palmitoyl-AP1 (PAP1 ; hydrolyzed fumonisin B1 alsonamed AP1 for aminopentol). As outlined by Humpf et al. (1998), a somewhat unexpected finding ofthis study was that PAP1 was highly cytotoxic for HT29 cells, and a more potent inhibitor of ceramidesynthase, causing sphinganine accumulation. In vivo acylation was also evaluated in rats, and whileformation of N-acyl-AP1 occurs and produces metabolites with fatty acids of various chain lengths,no toxicity was observed (Seiferlein et al., 2007). Considering observations of Humpf and Seiferlein,we cannot exclude in our experiment that acylation did not occur, but neither increase insphinganine concentrations nor toxicity was detected. Nonetheless, this aspect warrants furtherinvestigations, considering that there are multiple of isoforms of ceramide synthase (CerS) that aredifferently expressed according to tissues and differ in fatty acyl-CoA selectivity. Besides, a differentoutcome depending on animal species does not have to be excluded.To conclude, we showed for the first time in domestic animals that the hydrolyzed form of FB1 ismuch less toxic than the parent compound, and therefore confirmed results observed in rodentsexposed to pure HFB1. Furthermore, the HFB1 in this study was originally obtained after anenzymatic treatment on FB1 with a carboxylesterase. It is thus of concern to consider the potential ofthese biotransformation approaches in order to counteract adverse effects of FB1-contaminatedfeed in farms. Recently, it has also been suggested that the carboxylesterase could be combined withan enzyme, expressed from the same cluster gene of the carboxylesterase FumD (Heinl et al., 2010;140