Hydrolytic Fate of 3/15-Acetyldeoxynivalenol in Humans: Specific Deacetylation by the Small Intestine and Liver Revealed Using in Vitro and ex Vivo Approaches

Abstract

In addition to deoxynivalenol (DON), acetylated derivatives, i.e., 3-acetyl and 15-acetyldexynivalenol (or 3/15ADON), are present in cereals leading to exposure to these mycotoxins. Animal and human studies suggest that 3/15ADON are converted into DON after their ingestion through hydrolysis of the acetyl moiety, the site(s) of such deacetylation being still uncharacterized. We used in vitro and ex vivo approaches to study the deacetylation of 3/15ADON by enzymes and cells/tissues present on their way from the food matrix to the blood in humans. We found that luminal deacetylation by digestive enzymes and bacteria is limited. Using human cells, tissues and S9 fractions, we were able to demonstrate that small intestine and liver possess strong deacetylation capacity compared to colon and kidneys. Interestingly, in most cases, deacetylation was more efficient for 3ADON than 15ADON. Although we initially thought that carboxylesterases (CES) could be responsible for the deacetylation of 3/15ADON, the use of pure human CES1/2 and of CES inhibitor demonstrated that CES are not involved. Taken together, our original model system allowed us to identify the small intestine and the liver as the main site of deacetylation of ingested 3/15ADON in humans.

Masked trichothecene and zearalenone mycotoxins withstand digestion and absorption in the upper GI tract but are efficiently hydrolyzed by human gut microbiota in vitro

“…The results in the present study are in agreement with findings in the literature indicating that DON3Glc and T2Glc are stable under upper GI conditions in vitro . Acetylated DON has also been found to be stable to digestive enzymes in vitro . One in vivo study in rats confirms the stability of DON3Glc in the small intestine, but authors report hydrolysis of ZEN14Glc to free ZEN as early as the stomach .…”

“…However, lower bioavailability of NIV compared to DON has been reported in broilers [38] and further studies will be required to elucidate possible differences in absorption and the potential role of efflux pumps. We found no evidence of metabolism of DON by intestinal cells, but deacetylation of acetylated DON by small intestinal preparations has been shown recently [30]. Our findings of the efficient transport of T2/HT2 demonstrate high bioavailability of these potent type-A trichothecenes.…”

Deoxynivalenol: Masked forms, fate during food processing, and potential biological remedies

“…(c) Metabolism of D3G in pigs (Zhang et al., 2019). (d) Deacetylation of 3‐ADON and 15‐ADON in humans (Ajandouz et al., 2016)…”

“…Digestive enzymes, bacteria, intestinal, liver, and colon participated in the deacetylation process, and only free DON was found in the systemic blood. Once consumed, 3% and 7%, 10% and 26%, 2.6% and 0.9%, 26% and 13%, 1.7% and 0.7%, and 56% and 52% of 3‐ADON and 15‐ADON were deacetylated by pepsin, pancreatic enzymes, colonic bacteria, small intestine, colon, and liver, respectively, resulting in no acetylation forms in the whole blood circulation (Ajandouz et al., 2016).…”

Development of an Analytical Method for Simultaneous Determination of the Modified Forms of 4,15-Diacetoxyscirpenol and their Occurrence in Japanese Retail Food

“…Some analytical methods for the simultaneous determination of DON and its modified forms have been developed and their occurrence in food commodities have been reported [ 12 , 13 , 14 ]. Recent studies showed that these modified forms of DON were metabolized into DON in vivo, which may exert the same toxic effects as DON [ 15 , 16 ]. In 2017, the European Food Safety Agency (EFSA) evaluated the risk of DON and its modified forms and set a group-TDI for the sum of DON, 3ADON, 15ADON and D3G [ 17 ].…”