The Fusarium metabolite culmorin suppresses the in vitro glucuronidation of deoxynivalenol

Abstract

Glucuronidation is a major phase II conjugation pathway in mammals, playing an important role in the detoxification and biotransformation of xenobiotics including mycotoxins such as deoxynivalenol (DON). Culmorin (CUL), a potentially co-occurring Fusarium metabolite, was recently found to inhibit the corresponding detoxification reaction in plants, namely DON-glucoside formation, raising the question whether CUL might affect also the mammalian counterpart. Using cell-free conditions, CUL when present equimolar (67 µM) or in fivefold excess, suppressed DON glucuronidation by human liver microsomes, reducing the formation of DON-15-glucuronide by 15 and 50%, and DON-3-glucuronide by 30 and 50%, respectively. Substantial inhibitory effects on DON glucuronidation up to 100% were found using the human recombinant uridine 5′-diphospho-glucuronosyltransferases (UGT) 2B4 and 2B7, applying a tenfold excess of CUL (100 µM). In addition, we observed the formation of a novel metabolite of CUL, CUL-11-glucuronide, identified for the first time in vitro as well as in vivo in piglet and human urine samples. Despite the observed potency of CUL to inhibit glucuronidation, no significant synergistic toxicity on cell viability was observed in combinations of CUL (0.1–100 µM) and DON (0.01–10 µM) in HT-29 and HepG2 cells, presumably reflecting the limited capacity of the tested cell lines for DON glucuronidation. However, in humans, glucuronidation is known to represent the main detoxification pathway for DON. The present results, including the identification of CUL-11-glucuronide in urine samples of piglets and humans, underline the necessity of further studies on the relevance of CUL as a potentially co-occurring modulator of DON toxicokinetics in vivo. Electronic supplementary material The online version of this article (10.1007/s00204-019-02459-w) contains supplementary material, which is available to authorized users.

Fullerol C60(OH)24 Nanoparticles Affect Secondary Metabolite Profile of Important Foodborne Mycotoxigenic Fungi In Vitro

“…At the moment, the role of sambucinol, a major metabolite of F. culmorum, is unknown. However, there is evidence that culmorin can seriously affect the deoxynivalenol metabolism in mammals by suppressing glucuronidation [47]. Equisetin is a secondary metabolite of F. verticillioides detected in growth media after addition of 100 and 1000 ng mL −1 of FNP (Figure 6a-2).…”

Twenty-Eight Fungal Secondary Metabolites Detected in Pig Feed Samples: Their Occurrence, Relevance and Cytotoxic Effects In Vitro

“…Interestingly, its natural occurrence is always correlated to the occurrence of DON. A recent study showed that CUL is able to inhibit the glucuronidation of DON in human liver microsomes, and thus, its detoxification process [64,65]. These findings make the compound highly relevant regarding synergistic effects, not only for the detoxification of DON, but also for other toxins.…”

Multiple Fungal Metabolites Including Mycotoxins in Naturally Infected and Fusarium-Inoculated Wheat Samples

“…According to one study [51] CULM, 15-hydroxyculmorin, 5-hydroxyculmorin, and 15-hydroxyculmoron were detected after inoculation with F. graminearum, showing enhanced DON toxicity to insects, impacting both growth and mortality, although according to some researchers, CULM and DON can have a synergistic effect on toxicity [52]. Recent findings indicate that CULM can suppress the activity of uridine diphosphate glucosyltransferases (UGTs) that catalyze the glycosylation of DON into the less toxic DON 3-glucoside (D3G) [15]. Compared to DON, in the current research, D3G was found in lower concentrations.…”